Hypolipidemic 1,4-benzothiazepine-1,1-dioxides

ABSTRACT

The invention is concerned with novel hypolipidemic compounds of formula (I), with processes and novel intermedites for their preparation, pharmaceutical compositions containing them and with their use in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions, such as atherosclerosis. ##STR1##

This application has been filed under 35 USC 371 as a national stageapplication of PCT/GB95/01884, filed Aug. 9, 1995.

The present invention is concerned with new hypolipidemic compounds,with processes and novel intermediates for their preparation, withpharmaceutical compositions containing them and with their use inmedicine, particularly in the prophylaxis and treatment ofhyperlipidemic conditions, such as atherosclerosis.

Hyperlipidemic conditions are often associated with elevated plasmaconcentrations of low density lipoprotein (LDL) cholesterol and very lowdensity lipoprotein (VLDL) cholesterol. Such concentrations can bereduced by decreasing the absorption of bile acids from the intestine.One method by which this may be achieved is to inhibit the bile acidactive uptake system in the terminal ileum. Such inhibition stimulatesthe conversion of cholesterol to bile acid by the liver and theresulting increase in demand for cholesterol produces a correspondingincrease in the rate of clearance of LDL and VLDL cholesterol from theblood plasma or serum.

There has now been identified a novel class of heterocyclic compoundswhich reduce the plasma or serum concentrations of LDL and VLDLcholesterol and in consequence are particularly useful as hypolipidemicagents. By decreasing the concentrations of cholesterol and cholesterolester in the plasma, the compounds of the present invention retard thebuild-up of atherosclerotic lesions and reduce the incidence of coronaryheart disease-related events. The latter are defined as cardiac eventsassociated with increased concentrations of cholesterol and cholesterolester in the plasma or serum.

For the purposes of this specification, a hyperlipidemic condition isdefined as any condition wherein the total cholesterol concentration(LDL+VLDL) in the plasma or serum is greater than 240 mg/dL (6.21mmol/L) (J. Amer. Med. Assn. 256, 20, 2849-2858 (1986)).

International Patent Application No. WO 93/16055 describes compounds offormula (O) ##STR2## wherein 1 is an integer of from 0 to 4;

m is an integer of from 0 to 5;

n is an integer of from 0 to 2;

R and R' are atoms or groups independently selected from halogen, nitro,phenylalkoxy,

C₁₋₄ alkoxy, C₁₋₆ alky, and --O(CH₂)_(p) SO₃ R" wherein p is an integerof from 1 to 4 and

R" is hydrogen or C₁₋₆ alky, wherein said phenylalkoxy, alkoxy and allgroups are optionally substituted by one or more halogen atoms;

R^(a) is a C₁₋₆ straight, that is, unbranched, alkyl group; and

R^(b) is a C₂₋₆ straight, that is, unbranched, alkyl group; and salts,solvates and physiologically functional derivatives thereof, as beinguseful as hypolipidemic agents.

We have now discovered a group of compounds which have greaterhypolipidemic activity in vivo than those specifically disclosed inInternational Patent Application No. WO 93/16055.

Accordingly the present invention provides compounds of the formula (I):##STR3## wherein R¹ is a straight chained C₁₋₆ alkyl group; R² is astraight chained C₁₋₆ alkyl group; R³ is hydrogen or a group OR¹¹ inwhich R¹¹ is hydrogen, optionally substituted C₁₋₆ alkyl or a C₁₋₆alkylcarbonyl group; R⁴ is pyridyl or optionally substituted phenyl; R⁵,R⁶, R⁷ and R⁸ are the same or different and each is selected fromhydrogen, halogen, cyano, R¹⁵ -acetylide, OR¹⁵, optionally substitutedC₁₋₆ alkyl, COR¹⁵, CH(OH)R¹⁵, S(O)_(n) R¹⁵, P(O)(OR¹⁵)₂, OCOR¹⁵, OCF₃,OCN, SCN, NHCN, CH₂ OR¹⁵, CHO, (CH₂)_(p) CN, CONR¹² R¹³, (CH₂)_(p) CO₂R¹⁵, (CH₂)_(p) NR¹² R¹³, CO₂ R¹⁵, NHCOCF₃, NHSO₂ R¹⁵, OCH₂ OR¹⁵,OCH═CHR¹⁵, O(CH₂ CH₂ O)_(n) R¹⁵, O(CH₂)_(p) SO₃ R¹⁵, O(CH₂)_(p) NR¹² R¹³and O(CH₂)_(p) N⁺ R¹² R¹³ R¹⁴ wherein p is an integer from 1-4, n is aninteger from 0-3 and, R¹², R¹³, R¹⁴ and R¹⁵ are independently selectedfrom hydrogen and optionally substituted C₁₋₆ alkyl; or R⁶ and R⁷ arelinked to form a group ##STR4## wherein R¹² and R¹³ are as hereinbeforedefined and m is 1 or 2; and R⁹ and R¹⁰ are the same or different andeach is hydrogen or C₁₋₆ alkyl; and salts, solvates or a physiologicallyfunctional derivatives thereof, with the proviso that when R³ ishydrogen either R⁷ is not hydrogen or at least two of R⁵, R⁶, R⁷ and R⁸are not hydrogen; and salts, solvates, and physiologically functionalderivatives thereof.

When R⁴ is a substituted phenyl group, there may be one to five,preferably one or two substituents which are the same or different andare each selected from halogen, hydroxy, nitro, phenyl-C₁₋₆ alkoxy, C₁₋₆alkoxy, optionally substituted C₁₋₆ alkyl, S(O)_(n) R¹⁵, CO₂ R¹⁵, O(CH₂CH₂ O)_(n) R¹⁵, O(CH₂)_(p) SO₃ R¹⁵, O(CH₂)_(p) NR¹² R¹³ and O(CH₂)_(p)N⁺ R¹² R¹³ R¹⁴ wherein R¹² to R¹⁵, n and p are as hereinbefore defined.

According to a further aspect, the invention provides compounds offormula (I) wherein:

R¹ and R² are straight chained C₁₋₆ alkyl;

R³ is hydrogen or hydroxy;

W⁴ is unsubstitued pheryl;

R⁵ is hydrogen;

R⁹ and R¹⁰ are both hydrogen; and either

R⁷ is selected from halogen, hydroxy, C₁₋₆ alkoxy, optionallysubstituted C₁₋₆ alkyl, --S(O)_(n) R¹⁵, --OC(O)R¹⁵, and --CH₂ OR¹⁵wherein R¹⁵ is hydrogen or C₁₋₆ alkyl; and

R⁶ and R⁸ are independently selected from hydrogen and those groupslisted in the definition of R⁷ ; or

R⁸ is hydrogen and R⁶ and R⁷ are linked to form a group --O--(CH₂)_(m)--O-- wherein m is 1 or 2;

and salts, solvates, and physiologically functional derivatives thereof

Of the compounds of formula (I), those in which R⁸ is hydrogen and R⁶and R⁷ are both C₁₋₆ alkoxy, more particularly both methoxy, arepreferred.

Preferred embodiments of the compounds of formula (I) include compoundsof the formula (II), (III), (IV) or (IVa) ##STR5## wherein R¹ to R¹⁰ areas hereinbefore defined and R^(7a) is selected from halogen, cyano, R¹⁵-acetylide, OR¹⁵, optionally substituted C₁₋₆ alkyl, COR¹⁵, CH(OH)R¹⁵,S(O)_(n) R¹⁵, P(O)(OR¹⁵)₂, OCOR¹⁵, OCF₃, OCN, SCN, HNCN, CH₂ OR¹⁵, CHO,(CH₂)_(p) CN, CONR¹² R¹³, (CH₂)_(p) CO₂ R¹⁵, (CH₂)_(p) NR¹² R¹³, CO₂R¹⁵, NHCOCF₃, NHSO₂ R¹⁵, OCH₂ OR¹⁵, OCH═CHR¹⁵, O(CH₂ CH₂ O)_(p) R¹⁵,O(CH₂)_(p) SO₃ R¹⁵, O(CH₂)_(p) NR¹² R¹³ and O(CH₂)_(p) N⁺ R¹² R¹³ R¹⁴wherein n, p and R¹² to R¹⁵ are as hereinbefore defined; with theproviso that in compounds of formula (III) at least two of R⁵ to R⁸ arenot hydrogen; and salts solvates and physiologically functionalderivatives thereof

When one or more of R³ to R⁸ or R¹¹ to R¹⁴ is a substituted C₁₋₆ alkylgroup, or comprises a C₁₋₆ alkyl group the substituents may be the sameor different and each is selected from hydroxy, halogen, C₁₋₆ alkyl,C₁₋₆ alkoxy, COR¹⁶, nitrile, CO₂ R¹⁶, SO₃ R¹⁶, NR¹⁷ R¹⁸, N⁺ R¹⁷ R¹⁸ R¹⁹wherein R¹⁶ to R¹⁹ are the same or different an each is selected fromhydrogen or C₁₋₆ alkyl.

Suitably R¹ is methyl, ethyl or n-propyl and preferably R¹ is ethyl.Suitably R² is methyl, ethyl, n-propyl, n-butyl or n-pentyl. PreferablyR² is n-butyl.

Preferably R⁵ is hydrogen.

Suitably R⁷ and R^(7a) are selected from OR¹⁵, S(O)_(n) R¹⁵, OCOR¹⁵,OCF₃, OCN, SCN, CHO, OCH₂ OR¹⁵, OCH═CHR¹⁵, O(CH₂ CH₂ O)_(n) R¹⁵,O(CH₂)_(p) SO₃ R¹⁵, O(CH₂)_(p) NR¹² R¹³ and O(CH₂)_(p) N⁺ R¹² R¹³ R¹⁴wherein p is an integer from 1-4, n is an integer from 0-3 and, R¹²,R¹³, R¹⁴ and R¹⁵ are independently selected from hydrogen and optionallysubstituted C₁₋₆ alkyl. Preferably R⁷ and R^(7a) are OR¹⁵.

Suitably R⁹ and R¹⁰ are hydrogen, methyl or ethyl. Preferably R⁹ and R¹⁰are both hydrogen.

Suitably R⁴ is pyridyl or phenyl optionally substituted, preferably atthe 4- and/or 3-position by halogen, methyl, ethyl, methoxy, ethoxy,trifluoromethyl, hydroxy, carboxy or O(CH₂)₃ SO₃ H Perferably R⁴ isunsubstituted phenyl.

In the compounds of the formula (II): suitably one or two, andpreferably one, of R⁵, R⁶ and R⁸ is other than hydrogen and suitablyeach is selected from C₁₋₄ alkyl, optionally substituted by fluoro, C₁₋₄alkoxy, halogen and hydroxy. Most suitably, each is selected frommethyl, methoxy, hydroxy, trifluoromethyl and halo. Preferably, R⁶ ismethoxy or bromo and R⁵ and R⁸ are hydrogen. Suitably, R^(7a) is C₁₋₄alkyl optionally substituted by fluoro, C₁₋₄ alkoxy, halogen or hydroxy.Most suitably, R^(7a) is methoxy, hydroxy or trifluoromethyl andpreferably R^(7a) is methoxy.

In the compounds of the formula (III): suitably at least one andpreferably two of R⁵ to R⁸ are hydrogen. Preferably at least one of R⁶and R⁷ is not hydrogen. When R⁵ to R⁸ are other than hydrogen then theyare suitably C₁₋₄ alkyl optionally substituted by fluorine, C₁₋₄ alkoxy,halogen or hydroxy, most suitably methyl, methoxy, hydroxy,trifluoromethyl or chloro and preferably methoxy.

In the compounds of the formula (IV): suitably two, three or four of R⁵to R⁸ are hydrogen, the others being C₁₋₄ alkyl optionally substitutedby fluoro, C₁₋₄ alkoxy, halogen or hydroxy and most suitably methyl,methoxy, hydroxy, trifluoromethyl or chloro and preferably methoxy.

In the compounds of formula (IVa): suitably at least one and preferablytwo of R⁵ to R⁸ are hydrogen. Preferably at least one of R⁶ and R⁷ isnot hydrogen. When R⁵ to R⁸ are other than hydrogen then they aresuitably C₁₋₄ alkyl optionally substituted by fluorine, C₁₋₄ alkoxy,halogen or hydroxy, most suitably methyl, methoxy, hydroxy,trifluoromethyl or chloro and preferably methoxy. Most preferably, R¹ isn-butyl, R² is ethyl, R³, R⁵, R⁸, R⁹ and R¹⁰ are hydrogen, R⁴ is pyridylor optionally substituted phenyl and R⁶ and R⁷ are methoxy.

Preferred compounds of formula (I) are selected from the groupconsisting of:

(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetradhydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-4-ol1,1-dioxide;

(+-)-Trans-3-butyl-3ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-4-ol1,1-dioxide;

(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;

(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine4-ol1,1-dioxide;

(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7,8-diol1,1-dioxide;

(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-ol1,1-dioxide;

(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepine-8-ol1,1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-ol1,1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-carbaldehyde1,1-dioxide;

(+-)-Trans-2-((3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-yl)methoxy)ethanol S,S-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,4-benzothiazepine-7-carbaldehyde1,1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-thiol1,1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-sulfonicacid-1,1-dioxide;

(7R,9R)-7-Butyl-7-ethyl-6,7,8,9-tetrahydro-9-phenyl-1,3-dioxolo(4,5-H)(1,4)-benzothiazepine5,5-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

(3R,5R)-3-butyl-3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-7,8-dimethoxy-1,4-benzothiazpin-4-ol1,1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-methanolS,S-dioxide;

(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-nitro-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-(methoxymethyl)-5-phenyl-1,4-benzothiazepine1,1-dioxide;

(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7,8-diyldiacetate-1,1-dioxide;

(8R,10R)-8-Butyl-8-ethyl-2,3,7,8,9,10-hexahydro-10-1,4-dioxono(2,3-H)(1,4)-benzothiazepine6,6-dioxide;

(3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide;

(+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine1,1-dioxidehydrochloride;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-carbaldehyde-1,1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;

3,3-Diethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-8-methoxy-1,4-benzothiazepine1,1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4,8-diol1,1-dioxide;

(RS)-3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;

(+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4-ol-1,1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine-4-ol1,1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-1,4-benzothiazepine-4-ol1,1-dioxide;

(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4,7,8-triol1,1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;

(+-)-Trans-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-7,8-dimethoxy-1,4-benzothiazepine-4-ylacetate S,S-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-ol1,1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepine-8-ol1,1-dioxide;

3,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-ol1,1-dioxide;

(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepine-8-ylhydrogen sulfate;

(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepine-8-yldihydrogen phosphate;

3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepine-8-ylhydrogen sulfate;

3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepine-8-yl-dihydrogenphosphate;

(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepine-8-ylaspartate; and

3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepine-8-ylaspartate.

Pharmaceutically acceptable salts are particularly suitable for medicalapplications because of their greater aqueous solubility relative to theparent, ie basic, compounds. Such salts must clearly have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the present inventioninclude those derived from inorganic acids, such as hydrochloric,hydrobromic, phosphoric, metaphosphoric, nitric, sulphonic and sulphuricacids, and organic acids, such as acetic, benzenesulphonic, benzoic,citric, ethanesulphonic, fumaric, gluconic, glycollic, isothionic,lactic, lactobionic, maleic, malic, methanesulphonic, succinic,p-toluenesulphonic, tartaric and trifluoroacetic acids. The chloridesalt is particularly preferred for medical purposes. Suitablepharmaceutically acceptable base salts include ammonium salts, alkalimetal salts, such as sodium and potassium salts, and alkaline earthsalts, such as magnesium and calcium salts.

Salts having a non-pharmaceutically acceptable anion are within thescope of the invention as useful intermediates for the preparation orpurification of pharmaceutically acceptable salts and/or for use innon-therapeutic, for example, in vitro, applications.

The term "physiologically functional derivative" as used herein refersto any physiologically acceptable derivative of a compound of thepresent invention, for example, an ester, which upon administration to amammal, such as a human, is capable of providing (directly orindirectly) such a compound or an active metabolite thereof.

A further aspect of the present invention is prodrugs of the compoundsof the invention. Such prodrugs can be metabolised in vivo to give acompound according to the invention. These prodrugs may or may not beactive in their own right.

The compounds of the present invention can also exist in differentpolymorphic forms, for example, amorphous and crystalline polymorphicforms. All polymorphic forms of the compounds of the present inventionare within the scope of the invention and are a further aspect thereof.

The term "alkyl" as used herein refers, unless otherwise stated, to amonovalent straight or branched chain radical. Likewise, the term"alkoxy" refers to a monovalent straight or branched chain radicalattached to the parent molecular moiety through an oxygen atom. The term"phenylalkoxy" refers to a monovalent phenyl group attached to adivalent C₁₋₆ alkylene group which is itself attached to the parentmolecular moiety through an oxygen atom.

The compounds of formula (I) exist in forms wherein the carbon centres--C(R¹)(R²)-- and --CHR⁴ -- is/are chiral. The present inventionincludes within its scope each possible optical isomer substantiallyfree, i.e. as associated with less than 5%, of any other opticalisomer(s), and mixtures of one or more optical isomers in anyproportions, including racemic mixtures.

For the purposes of this specification, the absolute chiralities of theaforementioned carbon centres are given in the order --C(R¹)(R²)--, then--CHR⁴ --.

In those cases where the absolute stereochemistry at --C(R¹)(R²)-- and--CHR⁴ -- has not been determined, the compounds of the invention aredefined in terms of the relative positions of the R¹ /R² and H/R⁴substituents. Thus those compounds wherein the bulkier of the R¹ and R²substituents, i.e. the substituent of higher mass, and the R⁴substituent are both located on the same side of the thiazepine ring arereferred to herein as "cis", and those compounds in which the bulkier ofthe R¹ and R² substituents are located on opposite sides of the ring arereferred to as "trans" and are preferred. It will be evident to askilled person that both "cis" and "trans" compounds of the inventioncan each exist in two enantiomeric forms which are individuallydesignated "(+)-" or "(-)-" according to the direction of rotation of aplane of polarised light when passed through a sample of the compound.Cis or trans compounds of the invention in which the individualanantiomers have not been resolved are referred to herein using theprefix "(+-)-".

According to further aspects of the invention, there are also provided:

(a) compounds of formula (I) and pharmaceutically acceptable salts,solvates and physiologically functional derivatives thereof for use astherapeutic agents, particularly in the prophylaxis and treatment ofclinical conditions for which a bile acid uptake inhibitor is indicated,for example, a hyperlipidemic condition, such as atherosclerosis;

(b) pharmaceutical compositions comprising a compound of formula (I) orone of its pharmaceutically acceptable salts, solvates, orphysiologically functional derivatives, at least one pharmaceuticallyacceptable carrier and, optionally, one or more other physiologicallyactive agents;

(c) the use of a compound of formula (I) or of a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof in the manufacture of a medicament for the prophylaxis ortreatment of a clinical condition for which a bile acid uptake inhibitoris indicated, for example, a hyperlipidemic condition, such asatherosclerosis;

(d) a method of inhibiting the absorption of bile acids from theintestine of a mammal, such as a human, which comprises administering aneffective bile acid absorption inhibiting amount of a compound offormula (I) or of a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof to the mammal;

(e) a method of reducing the blood plasma or serum concentrations of LDLand VLDL cholesterol in a mammal, such as a human, which comprisesadministering an effective cholesterol reducing amount of a compound offormula (I) or of a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof to the mammal;

(f) a method of reducing the concentrations of cholesterol andcholesterol ester in the blood plasma or serum of a mammal, such as ahuman, which comprises administering an effective cholesterol andcholesterol ester reducing amount of a compound of formula (I) or of apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof to the mammal;

(g) a method of increasing the fecal excretion of bile acids in amammal, such as a human, which comprises administering an effective bileacid fecal excretion increasing amount of a compound of formula (I) orof a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof to the mammal;

(h) a method for the prophylaxis or treatment of a clinical condition ina mammal, such as a human, for which a bile acid uptake inhibitor isindicated, for example, a hyperlipidemic condition, such asatherosclerosis, which comprises administering a therapeuticallyeffective amount of a compound of the formula (I) or of apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof to the mammal;

(i) a method of reducing the incidence of coronary heart disease-relatedevents in a mammal, such as a human, which comprises administering aneffective coronary heart disease-related events reducing amount of acompound of formula (I) or of a pharmaceutically acceptable salt,solvate, or physiologically functional derivative thereof;

(j) a method of reducing the concentration of cholesterol in the bloodplasma or serum of a mammal, such as a human, which comprisesadministering an effective cholesterol reducing amount of a compound offormula (I);

(k) processes for the preparation of compounds of formula (I) (includingsalts, solvates and physiologically functional derivatives thereof asdefined herein); and

(l) novel chemical intermediates in the preparation of compounds offormula (I).

(m) the compounds of Synthetic Examples 1-53 as hereinafter disclosed.

Hereinafter all references to "compound(s) of formula (I)" refer tocompound(s) of formula (I) as described above together with their salts,solvates and physiologically functional derivatives as defined herein.

The amount of a compound of formula (I) which is required to achieve thedesired biological effect will, of course, depend on a number offactors, for example, the specific compound chosen, the use for which itis intended, the mode of administration and the clinical condition ofthe recipient. In general, a daily dose is in the range of from 0.3 mgto 100 mg (typically from 3 mg to 50 mg) per day per kilogrambodyweight, for example, 3-10 mg/kg/day. An intravenous dose can, forexample, be in the range of from 0.3 mg to 1.0 mg/kg, which canconveniently be administered as an infusion of from 10 ng to 100 ng perkilogram per minute. Infusion fluids suitable for this purpose cancontain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10mg, per millilitre. Unit doses can contain, for example, from 1 mg to 10g of the active compound. Thus ampoules for injection can contain, forexample, from 1 mg to 100 mg and orally administrable unit doseformulations, such as tablets or capsules, may contain, for example,from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case ofpharmaceutically acceptable salts, the weights indicated above refer tothe weight of the benzothiazepine ion derived from the salt.

For the prophylaxis or treatment of the conditions referred to above,the compounds of formula (I) can be used as the compound per se, but arepreferably presented with an acceptable carrier in the form of apharmaceutical composition. The carrier must, of course, be acceptablein the sense of being compatible with the other ingredients of thecomposition and must not be deleterious to the recipient. The carriercan be a solid or a liquid, or both, and is preferably formulated withthe compound as a unit-dose composition, for example, a tablet, whichcan contain from 0.05% to 95% by weight of the active compound. Otherpharmacologically active substances can also be present including othercompounds of formula (I). The pharmaceutical compositions of theinvention can be prepared by any of the well known techniques ofpharmacy consisting essentially of admixing the components.

Pharmaceutical compositions according to the present invention includethose suitable for oral, rectal, topical, buccal (e.g. sub-lingual) andparenteral (e.g. subcutaneous, intramuscular, intradermal, orintravenous) administration, although the most suitable route in anygiven case will depend on the nature and severity of the condition beingtreated and on the nature of the particular compound of formula (I)which is being used. Enteric-coated and enteric-coated controlledrelease formulations are also within the scope of the invention.Suitable enteric coatings include cellulose acetate phthalate,polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate andanionic polymers of methacrylic acid and methacrylic acid methyl ester.

Pharmaceutical compositions suitable for oral administration can bepresented in discrete units, such as capsules, cachets, lozenges, ortablets, each containing a predetermined amount of a compound of formula(I); as a powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water or water-in-oilemulsion. As indicated, such compositions can be prepared by anysuitable method of pharmacy which includes the, step bringing intoassociation the active compound and the carrier (which can constituteone or more accessory ingredients). In general, the compositions areprepared by uniformly and intimately admixing the active compound with aliquid or finely divided solid carrier, or both, and then, if necessary,shaping the product. For example, a tablet can be prepared bycompressing or moulding a powder or granules of the compound, optionallywith one or more accessory ingredients. Compressed tablets can beprepared by compressing, in a suitable machine, the compound in afree-flowing form, such as a powder or granules optionally mixed with abinder, lubricant, inert diluent and/or surface active/dispersingagent(s). Moulded tablets can be made by moulding, in a suitablemachine, the powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions suitable for buccal (sub-lingual)administration include lozenges comprising a compound of formula (I) ina flavored base, usually sucrose and acacia or tragacanth, and pastiliescomprising the compound in an inert base such as gelatin and glycerin orsucrose and acacia.

Pharmaceutical compositions suitable for parenteral administrationconveniently comprise sterile aqueous preparations of a compound offormula (I), preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration can also be effected by means of subcutaneous,intramuscular, or intradermal injection. Such preparations canconveniently be prepared by admixing the compound with water andrendering the resulting solution sterile and isotonic with the blood.Injectable compositions according to the invention will generallycontain from 0.1 to 5% w/w of the active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably presented as unit-dose suppositories. These can be preparedby admixing a compound of formula (I) with one or more conventionalsolid carriers, for example, cocoa butter, and then shaping theresulting mixture.

Pharmaceutical compositions suitable for topical application to the skinpreferably take the form of an ointment, cream, lotion, paste, gel,spray, aerosol, or oil. Carriers which can be used include vaseline,lanoline, polyethylene glycols, alcohols, and combinations of two ormore thereof The active compound is generally present at a concentrationof from 0.1 to 15% w/w of the composition, for example, from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal administration can be presented as discretepatches adapted to remain in intimate contact with the epidermis of therecipient for a prolonged period of time. Such patches suitably containthe active compound in an optionally buffered, aqueous solution,dissolved and/or dispersed in an adhesive, or dispersed in a polymer. Asuitable concentration of the active compound is about 1% to 35%,preferably about 3% to 15%. As one particular possibility, the activecompound can be delivered from the patch by electrotransport oriontophoresis, for example, as described in Pharmaceutical Research,3(6), 318 (1986).

The compounds of the invention can be prepared by conventional methodsknown to a skilled person or in an analogous manner to processesdescribed in the art.

For example, compounds of the formula (I) wherein R³ is hydrogen can beprepared by oxidation of the corresponding compound of the formula (V):##STR6## wherein R¹ to R¹⁰ are as hereinbefore defined and l is 0 or 1.This oxidation may suitably be carried out by reaction with a peroxide,for example hydrogen peroxide in the presence of trifluoroacetic acid ata non-extreme temperature, e.g. -20° C. to 50° C. and preferably at -10°C. to 10° C. The compound of the formula (V) where l is 1 may beprepared from the corresponding compound where l is 0 by partialoxidation using a peroxide as described above.

Compounds of formula (V) can be prepared by reducing the imine bond of acompound of formula (VI) ##STR7## wherein R¹ to R¹⁰ are as hereinbeforedefined, using, for example, a boron compound, such as borane, in asuitable solvent, for example an ether such as THF, or catalytichydrogenation using, for example, a palladium catalyst, such as 10% Pd/Cat a non-extreme temperature, for example -20° C. to 100° C. andpreferably -10° C. to 50° C.

Compounds of formula (VI) as herein defined as well as each possibleoptical isomer substantially free, i.e., associated with less than 5% ofany other optical isomer(s), and mixtures of one or more optical isomersin any proportions, including racemic mixtures are considered to benovel and constitute a further aspect of the present invention.

Compounds of formula (VI) can be prepared by cyclising compounds offormula (VII) ##STR8## wherein R¹ to R⁸ are as hereinbefore defined, by,for example, azeotropic distillation or refluxing in the presence of asuitable drying agent, such as molecular sieves, in a suitable solvent,for example, 2,6-lutidine, in the presence of an acid, such as HCl.

Compounds of formula (VII) can be prepared by reacting a compound offormula (VIII) ##STR9## wherein R⁴ to R⁸ are as hereinbefore defined,with the appropriately substituted aziridine, typically in a polarsolvent, for example, methanol.

Compounds of formula (VII) can also be prepared by reacting a compoundof formula (IX) ##STR10## wherein R⁴ to R⁸ are as hereinbefore definedand L is a suitable leaving group, for example, halogen, with a compoundof formula HSC(R⁹)(R¹⁰)C(R¹)(R²)Nh₂ wherein R¹,R² R⁹ and R¹⁰ are ashereinbefore defined.

Compounds of formula (IX) can be prepared by reacting the correspondingacid with a compound of formula R⁴ H wherein R⁴ is as hereinbeforedefined, typically by a Friedel-Crafts reaction using, for example,aluminium chloride.

Compounds of formula (VIII) can be prepared by reacting a compound offormula (X) ##STR11## wherein R⁵ to R⁸ are as hereinbefore defined witha non-nucleophilic base such as sodium hydride followed by treatment ofthe resulting salt with N,N-dimethylthiocarbamoyl chloride, pyrolysis ofthe resulting O-aryldialkylthiocarbamate to theS-aryldialkylthiocarbamate (for example in a high boiling solvent suchas tetradecane at a temperature of about 255° C.), and hydrolysis (forexample with a strong base such as KOH).

Alternatively, compounds of formula (VIII) can be prepared by reactingcompounds of formula (IX) with sodium hydrosulfide (NaSH).

The starting materials as hereinbefore defined can be obtainedcommercially or prepared by methods known to those skilled in the art orobtainable from the chemical literature, for example, the aziridines canbe prepared from the corresponding 2-substituted 2-aminoethanols.

Compounds of the formula (V) wherein one or more of R⁵ to R⁸ is halo maybe converted to compounds of the formula (V) wherein R⁵ to R⁸ is adifferent functional group by methods known to those skilled in the artor readily available from the literature.

Compounds of formula (I) wherein R³ =OH can be prepared from thecorresponding compounds of formula (I) wherein R³ =H by oxidation with,for example, m-chloroperbenzoic acid.

The compounds of formula (I) substantially free, of other opticalisomers can be obtained either by chiral synthesis, for example, by theuse of the appropriate chiral starting material(s), such as theaziridine, or by resolution of the products obtained from aciralsyntheses, for example, by chiral hplc or by classical resolution withchiral acids.

Optional conversion of a compound of formula (I), or a compound offormula (I) comprising a basic substituent, to a corresponding acidaddition salt may be effected by reaction with a solution of theappropriate acid, for example, one of those recited earlier. Optionalconversion of a compound of formula (I) comprising an acidic substituentto a corresponding base salt may be effected by reaction with a solutionof the appropriate base, for example, s odium hydroxide. Option alconversion to a physiologically functional derivative, such as an ester,can be carried out by methods known to those skilled in the art orobtainable from the chemical literature.

In addition, compounds of the formula (I) may be converted to differentcompounds of the formula (I) by standard methods known or available fromthe literature to those skilled in the art, for example by alkylation ofa hydroxy group.

For a better understanding of the invention, the following Examples aregiven by way of illustration and are not to be construed in any way aslimiting the scope of the invention.

SYNTHETIC EXAMPLE 1 Preparation of(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1-4-benzothiazepine1,1-dioxide

(a) Ethyl 2-aminobutyate hydrochloride

A slurry of 2-aminobutyric acid (100 g, Aldrich) in absolute ethanol(300 ml) wa s stirred under nitrogen at 0° C. and thionyl chloride(120.8 g) was added dropwise. The reaction was stirred overnight at 0°C. and then gradually warmed to room temperature. The resulting whiteslurry was heated under reflux for 3 hours, left to cool for 10 minutes,then poured into chilled diethyl ether (600 ml), with hand stirring. Thesuspension was filtered and the solid product dried to give the desiredproduct (150 g) as a white solid. ¹ H NMR consistent with proposedstructure.

(b) Ethyl 2-benzylideneamnobutyrate

A solution of the product from step (a) (149.6 g), magnesium sulfate(74.3 g), and triethylamine (246 ml) in dichtoromethane (1500 ml) wasstirred at room temperature under nitrogen and benzaldehyde (94.9 g,Aldrich) was added dropwise. The mixture was stirred at room temperaturefor 3 hours then filtered. The filtrate was concentrated, triturated indiethyl ether, filtered and concentrated to yield the desired product asa yellow oil (174 g), ¹ H NMR consistent with the proposed structure.

(c) (+-)-Ethyl 2-benzylideneamino-2-ethylhexanoate

Sodium hydride (32.5 g, 60% dispersion in oil) and N,N-dimethylfomiamide(DMF) (700 ml) were stirred under nitrogen at room temperature and asolution of the product from step (b) (178.1 g) in DMF was addeddropwise. After 2 hours stirring at room temperature, a solution ofbutyl iodide (149.5 g) in DMF was added dropwise and the reaction leftstirring for a further 2 hours. The reaction was poured into an ice coldmixture of water (560 ml), diethyl ether (300 ml) and ammonium chloride(120 g). The resulting organic layer was dried over potassium carbonatethen concentrated to give the desired product as a brown oil (220 g).

(d) (+-)-Ethyl 2-amino-2-ethylhexanoate

The product from step (c) (233.0 g) was partitioned between petroleumether and 10% w/w hydrochloric acid (421 ml) and stirred at roomtemperature for 2 hours. The aqueous layer was extracted twice withpetroleum ether and then chilled with ethyl acetate in an ice-salt bath.Sodium hydroxide pellets were added to the mixture until the aqueouslayer was at pH 10. The latter was extracted twice with ethyl acetateand the combined ethyl acetate layers were dried over potassiumcarbonate, then concentrated and vacuum distilled to give the desiredproduct as a colourless oil. ¹ H NMR consistent with the proposedstructure.

(e) (R)-2-Amino-2-ethylhexanoic acid

A suspension of pig liver esterase (0.1 g, Sigma-Aldrich-Fluka) in waterwas added to an aqueous solution of the product from step (d) (100 g).When addition was complete, the pH of the mixture was adjusted to 9.7using 1N aqueous NaOH and maintained at this value by the addition offurther 1N NaOH. After the addition of a predetermined amount of 1Naqueous NaOH (85 g over 10 hours), the mixture was washed with diethylether to remove unreacted (S)-ethyl 2-amino-2-ethyl-hexanoate. Theremaining aqueous phase was evaporated in vacuo to give a white solidcomprising the titled compound and its sodium salt.

(f) (R)-2-Amino-2-ethylhexan-1-ol

The product (20 g) from step (e) was added to a 1M solution of lithiumaluminum hydride (1.5 molar equivalents) in THF and the mixture wasrefluxed for 3 hours, then stirred for 16 hours at room temperature. Themixture was cooled to about 0° C., then quenched with water and 1Naqueous NaOH. The resulting solid was broken up with additional waterand the suspension was heated at 50° C. for 5 minutes, then cooled toroom temperature. Diethyl ether (100 ml) was added, the mixture wasstirred and filtered. The diethyl ether layer was separated, dried andconcentrated in vacuo to give the desired product as an oil (82% yield),¹ H NMR consistent with the proposed structure.

(g) (R)-2-Amino-2-ethylhexyl hydrogen sulfate

The product (20.0 g) from step (f) was dissolved in dichioromethane (170ml) and treated with chlorosulfonic acid (26.8 g). The reaction mixturewas stirred at room temperature for 17 hours. A major part of thesolvent was removed by distillation and the resulting slurry was dilutedwith acetone, filtered and dried to get a white solid. ¹ H NMRconsistent with the proposed structure.

(h) 2-Hydroxy-4,5-dimethoxybenzaldehyde

A 1.0M solution of boron trichloride (210 ml, Aldrich) indichloromethane was added to benzoyl chloride (130 g. Aldrich) inbenzene (350 ml). Next, 3,4-dimethoxyphenol (30.0 g, Aldrich) in benzene(130 ml) was added and the reaction mixture was stirred at roomtemperature for 21/2 hours. 50% NaOH (55 ml) was then added and themixture was stirred for 15 minutes. The organic layers were separated,dried and concentrated in vacuo. The resulting residue was trituratedwith ¹ N NaOH for 40 minutes then filtered. The aqueous basic filtratewas acidified with conc. HCl to give the title product as a yellow solid(25.9 g), mp 104-105° C. ¹ H NMR was consistent with the proposedstructure.

(i) O-(2-Benzoyl4,5-dimethoxyphenyl N,N-diethylthiocarbamate

Triethylamine (106.3 g, Aldrich)), 4-dimethylaminopyridine (6.5 g,Aldrich) and diethylthiocarbamoyl (86.4 g) was added to the product(130.4 g) from step(h) to 1 L of dioxane. The reaction mixture wasstirred at reflux for 22 hours, cooled to room temperature, thenfiltered. The filtrate was concentrated in vacuo and 1N HCl (600 ml) wasadded followed by diethyl ether (500 ml). The mixture was allowed tostand for 45 minutes, then filtered. The solids were washed thoroughlywith diethyl ether and dried in a vacuum oven to afford the titleproduct as a yellow solid (120.5 g), mp 94-95° C. ¹ H NMR was consistentwith the proposed structure.

(j) S-(2-Benzoyl-4,5-dimethoxyphenyl) N,N-diethylthiocarbamate

A slurry of the product (60.4 g) from step (i) in tetradecane (250 ml)was heated to an internal temperature of 250° C. and kept there for aperiod of 25 minutes. The reaction mixture was cooled with an ice bath.The solvent was decanted and the residue was triturated with diethylether (100 ml) to give the title product (43.4 g) as a beige solid, mp114-116° C. ¹ H NMR was consistent with the proposed structure.

(k) 2-Mercapto4,5-dimethoxybenzophenone

Potassium hydroxide pellets (58.6 g) was slowly added to a solution ofthe product (85.0 g) from step (j) dissolved in 1 L of methanol/THF(1:1). After refluxing for 3 hours, the reaction mixture was cooled toroom temperature and concentrated in vacuo. The resulting residue wastriturated with 1N HCl then extracted with EtOAc. The organic layer wasseparated, washed with 2×250 ml of 1N HCl then washed with 3×400 ml of1N NaOH. The aqueous basic layers were combined and acidified with conc.HCl to afford the title product (54.8 g) as a gold solid. ¹ H NMR wasconsistent with the proposed structure.

(1),(R)-2-(2-Amino-2-ethylhexylthio)4,5-dimethoxybenzophenone

The product (48.8 g) from step (g) was dissolved in water (250 ml) andto this solution the product (54.2 g) from step (k) in butyl acetate(300 ml) was added. The reaction mixture was stirred and heated to aninternal temperature of 93° C. and NaOH (18.9 g) in water (250 ml) wasadded dropwise. After complete addition, the reaction was stirred anadditional 25 minutes at 93° C., then cooled to room temperature. Theorganic layer was separated, dried and concentrated to give the titleproduct (78.5 g) as an orange-brown oil. Treatment of the free base withethereal HCl afforded the hydrochloride salt as a light yellow solid, mp75-78° C. ¹ H NMR consistent with the proposed structure.

(m)(3R)-3-Butyl-3-ethyl-2,3-dihydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine

The product (78.0 g) from step (1) was dissolved in 2,6-lutidine (400ml), added p-toluenesulfonic acid (0.70 g) and the reaction mixture wasrefluxed using a Dean Stark trap. The reaction was refluxed for a periodof 22 hours during which time solvent was removed from the apparatus andthen replaced with fresh solvent. The reaction mixture was concentratedin vacuo and the residue was treated with 5% NaHCO₃ (300 ml) andEtOAc(300 ml). The EtOAc layer was separated, washed with brine, driedand concentrated in vacuo to give a dark red oil. Chromatography onsilica gel, using hexane: EtOAc(4:1) as eluant, afforded the desiredproduct (64.1 g) as a light brown oil. ¹ H NMR consistent for theproposed structure.

(n)(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine

A 1M solution of diborane in THF (200 ml) was added to a solution of theproduct (64.0 g) from step (m) in THF (350 ml). The reaction mixture wasstirred at room temperature for a period of 17 hours, then 6N HCl (150ml) was added and the solution was concentrated in vacuo to remove THF.The aqueous residue was basified with 50% NaOH and extracted with EtOAc.The EtOAc layer was separated, dried and concentrated in vacuo to affordan oil which was chromatographed on silica gel, using hexane: EtOAc(85:15) as eluant, to give the title product (25.5 g) as a beige solid,mp 64-66° C. ¹ H NMR consistent for proposed structure.

(o)(3R,5R)-3-Butyl-1-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide

A solution of the product (25.5 g) from step (n) in trifluoroacetic acid(125 ml) was added to 30% H₂ O₂ (18.8 g) in trifluoroacetic acid (100ml). The reaction mixture was stirred at room temperature for 17 hours,then poured into water (800 ml) followed by the addition of 50% NaOHuntil the mixture reached a pH of 10. The reaction mixtre was layeredwith EtOAc and stirred for 1 hour. The organic layer was separated,dried and concentrated in vacuo to afford solids which wererecrystallized from EtOH to afford the title product (18.5 g) as a whitesolid, mp 148-149° C.

Analysis: Calcd: C 66.16; H 7.48; N 3.35; S 7.68; Found: C 66.01; H7.56; N 3.31; S 7.74;

¹ H NMR (DMSO-d₆), δ; 0.74-0.86(6H, m); 1.07-1.39 (4H, m); 1.39-2.20(4H, m); 3.33 (2H, q); 3.44 (3H, s); 3.83 (3H, s); 5.92 (1H, d); 6.11(1H, s); 7.33-7.48 (6H, m).

SYNTHETIC EXAMPLE 2 Preparation of(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-4-ol1,1-dioxide

Oxone (146.7 g Aldrich) in water (550 ml) was added to a solution of theproduct (18.4 g) from Synthetic Example 1(n) in MeOH (500 ml). Thereaction mixture was stirred at room temperature for 17 hours, thencautiously basified with 50% NaOH. This heterogeneous mixture waslayered with EtOAc and stirred for 1 hour. The organic layer wasseparated, dried and concentrated in vacuo to get a pink solid.Chromatography on silica gel, using hexane: EtOAc (65.35) as eluant,afforded the title product (6.7 g) as a white solid, mp 174-175° C.

Analysis: Calcd: C 63.72; H 7.21; N 3.23; S 7.39; Found: C 63.81; H7.22; N 3.19; S 7.47;

¹ H NMR(DMSO-d₆), δ: 0.77-0.90 (6H, m); 1.10-2.17 (8H,m); 3.27-3.45 (5H,m); 3.84 (3H, s); 6.14 (1H, s); 6.38 (1H, s); 7.30-7.53 (5H, m); 7.97(1H, s).

SYNTHETIC EXAMPLE 3 Preparation of(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide

(a) (+-)-2-Amino-2-ethylhexan-1-ol

Lithium aluminum hydride (22.2 g) was added to anhydrous diethyl ether(450 ml) under nitrogen. The product (129.0 g) from Synthetic Example1(d) was diluted with diethyl ether (40 ml) and added dropwise. Thereaction was refluxed for 1 hour then cooled to room temperature. 1Msodium hydroxide (23 ml) was added dropwise followed by deionised water.The resulting suspension was filtered and the filtrate concentrated togive the desired product as a colorless oil (87.9 g). ¹ H NMR consistentwith the proposed structure.

(b) (+-)-2-Butyl-2-ethylaziridine

Acetonitrile (150 ml) and the product (20.0 g) from step (a) were mixedunder nitrogen, cooled to 2-3° C. and chlorosulphonic acid (16.0 g)Aldrich) was added dropwise keeping the temperature below 10° C. Thecoolant was removed and the slurry left to stir for 80 minutes at roomtemperature. The reaction was concentrated in vacuo and co-distilledwith water (50 ml). 50% Aqueous sodium hydroxide (55.2 g) and water (50ml) were added and the mixture was distilled at atmospheric pressure.The organic layer was collected from the distillate and dried with solidpotassium hydroxide to give the desired product (12.8 g). ¹ H NMRconsistent with proposed structure.

(c)(+-)-3-Butyl-3-ethyl-2,3-dihydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine

The product (14.7 g) from Synthetic Example 1(k), in 2,6-lutidine (50ml), was added to a solution of the product (6.5 g) from step (b) in2,6-lutidine (200 ml). The reaction mixture was stirred for 1 hour,conc. HCl (4.4 ml) was added and then refluxed with a Dean-Stark trapfor 17 hours. The reaction mixture was concentrated in vacuo and theresidue was partitioned between 5% NaHCO, and EtOAc. The organic layerwas separated, dried and concentrated to get an oil which waschromatographed on silica gel, using hexane: EtOAc (7:3) as eluant toafford the desired product (12.0 g) as an oil. ¹ H NMR consistent withproposed structure.

d)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide

The title compound was prepared following the procedures of SyntheticExample 1 (n)-(o) using the product from step (c) to give a white solid,mp 146-147° C.

Analysis (0.50 H₂ O); Calcd: C 64.54; H 7.35; N 3.24; S 7.40; Found: C64.76; H 7.56; N 3.28; S 7.52; ¹ H NMR (DMSO-d₆), δ: 0.74-0.86 (6H, m);1.07-1.39 (4H, m); 1.40-2.20 (4H, m); 3.33 (2H, q); 3.44 (3H, s); 3.83(3H, s); 5.92 (1H d); 6.11 (1H, s); 7.30-7.48 (6H, m)

SYNTHETIC EXAMPLE 4 Preparation of(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-4-ol1,1-dioxide

Oxone (7.3 g, Aldrich) in water (100 ml) was added to a solution of theproduct (1.7 g) from Synthetic Example 3(d) in MeOH (100 ml). Thereaction mixture was stirred at room temperature for a period of 17hours and water and EtOAc were added. After stirring for 1 hour, theorganic layer was separated, dried and concentrated to give a foam.Chromatography on silica gel, using hexane: EtOAc (4:1) as eluant, gavethe desired product (1.2 g) as a white solid, mp 172-174° C.

Analysis: Calcd: C 63.72; H 7.21; N 3.23; S 7.39; Found: C 63.79; H7.26; N 3.18; S 7.47; ¹ H NMR (DMSO-d₆), δ: 0.78-0.90 (6H, m);1.14-2.14(8H, m); 3.27-3.41 (5H, m); 3.84 (3H, s); 6.13 (1H, s); 6.37(1H, s); 7.34-7.53 (5H, m); 7.96 (1H, s).

SYNTHETIC EXAMPLE 5 Preparation of(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide

(a) O-(2-benzoyl-5-methoxyphenyl)dimethylthiocarbamate

Sodium hydride (8.8 g, Aldrich) was added slowly to a solution of2-hydroxy-4-methoxybenzophenone (50.0 g, Aldrich) in 300 ml ofdimethylformamide. Hexamethylphosphoramiide (43.0 g) was then addeddropwise and stirred at room temperature for 2 hours.Dimethyithiocarbamoyl chloride (37.0 g, Aldrich) was added and stirredovernight at 50° C. The reaction mixture was poured into deionized water(300 mL) and extracted with a petroleum ether/chloroform (1:4) mixture.The organic layer was washed with 10% sodium hydroxide, brine andconcentrated to give the title product as a yellow solid (40.0 g). ¹ HNMR was consistent with proposed structure.

(b) S-(2-Benzoyl-5-methoxyphenyl)dimehylthiocarbamate

The product (97.4 g) from step (a) was suspended in tetradecane (500 mL)and heated to an internal temperature of 255° C. for 30 minutes. Aftercooling to room temperature, the reaction mixture was chromatographed onsilica gel using hexane, then hexanes/ethyl acetate (7:3) as eluants toafford the title product (65.0 g) as a tan solid, mp 95-97° C. ¹ H NMRwas consistent with proposed structure.

(c) 2-Mercapto-4-methoxybenzophenone

Potassium hydroxide pellets (20.0 g) were slowly added to a solution ofthe product (28.0 g) from step (b) dissolved in 800 mlmethanol/tetrahydrofuran (1:1). After refluxing for 4 hours, thereaction was cooled to room temperature, methylene chloride was addedand the solution was extracted with 5% hydrochloric acid. The organiclayer was dried and concentrated. Chromatography on silica gel usinghexanes/ethyl acetate (99:1) as the eluant afforded the title product(17.1 g) as an orange oil. ¹ H NMR consistent with proposed structure.

(d) (R)-2-(2-Amino-2-ethylhexylthio)-4-methoxyhenzophenone

This compound was prepared following the procedure of Synthetic Example1(1), using the product (46.4 g) from step (c) and the product (44.6 g)from Synthetic Example 1 (g). Concentration of the organic layerafforded the title product (66.5 g) as a red oil. ¹ H NMR consistentwith proposed structure.

(e)(3R)-3-Butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,4-benzothiazepine

This compound was prepared following the procedure of Synthetic Example1(m), using the product (66.5 g) from step (d). Chromatography on silicagel, using hexane:EtOAc (9:1) as eluant, afforded the title compound(54.5 g) as a yellow oil. ¹ H NMR consistent with the proposedstructure.

(f)(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine

This compound was prepared following the procedure of Synthetic Example1(n), using the product (54.4 g) from step (e). Chromatography on silicagel, using hexane:EtOAc (9:1) as eluant, gave the title product (22.8 g)as an orange oil. ¹ H NMR consistent with the proposed structure.

(g)(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine

Bromine (18.6 g) was added to a solution of the product (10.4 g) fromstep (f) dissolved in glacial acetic acid (150 ml). The reaction mixturewas stirred at room temperature for 2 hours. Acetic acid was removed invacuo, added another 100 ml and concentrated in vacuo. The resultingresidue was dissolved in EtOAc and washed with sodium metabisulfite and1N NaOH. The organic layer was separated, dried and concentrated invacuo to give a brown oil which was then converted to the hydrochloridesalt with ethereal HCl. This solid was filtered, washed with ether andthen treated with 1N NaOH and EtOAc to get the title product (8.9 g) asan orange oil. ¹ H NMR consistent with the proposed structure.

(h)(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide

This compound was prepared following the procedure of Synthetic Example1(o), using the product (8.2 g) from step (g). Chromatography on silicagel, using hexane: EtOAc (4:1) as eluant, afforded a foam which upontrituration in ether gave the title product (5.0 g) as a white solid, mp132-134° C.

Analysis: Calcd; C 56.65; H 6.05; N 3.00; Br 17.13; S 6.87; Found:C56.71; H 6.01; N 2.94; Br 17.07; S 6.95; ¹ HNMR (DMSO-d₆), δ: 0.64-0.81(6H, m); 0.97-1.19 (4H, m); 1.22-1.50 (2H, m) 1.69-1.78 (1H, m);1.98-2.06 (1H, m); 2.67 (1H, d,); 3.39 (2H, q,); 3.92 (3H, s); 5.88 (1H,d); 6.63 (1H, s); 7.29-7.43 (5H, m); 7.55 (1H, s)

SYNTHETIC EXAMPLE 6 Preparation of(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-4-ol1,1-dioxide

Meta-chloroperbenzoic acid (57-86%, 0.90 g, Aldrich) in CH₂ Cl₂ (50 ml)was added to a solution of the product (2.4 g) from Synthetic Example5(h) in CH₂ Cl₂ (50 ml). The reaction was stirred at room temperaturefor 1 hour, then 5% NaHCO₃ (100 ml) was added and the mixture stirredfor 30 minutes. The organic layer was separated, dried and concentratedin vacuo to give a foam. Chromatography on silica gel, using hexane:EtOAc (9:1) as eluant gave a foam which upon trituration with etherafforded the title product (1.3 g) as a white solid, mp 202-204° C.

Analysis: Calcd: C 54.77; H 5.85; N 2.90; Br 16.56; S 6.65; Found: C54.92; H 5.90; N 2.85; Br 16.65; S 6.75; ¹ H NMR (DMSO-d₆), δ: 0.75-0.86(6H, m); 1.05-1.41 (5H, m); 1.43-1.64 (1H, m); 1.66-1.79 (1H, m);1.83-2.49 (1H, m); 3.46 (2H, s); 3.93 (3H, s); 6.33 (1H, s); 6.67 (1H,s); 7.30-7.50 (6H, m); 8.07 (1H, s)

SYNTHETIC EXAMPLE 7 Preparation of(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7,8-diol1,1-dioxide

The product (5.0 g) from Synthetic Example 1(o) was dissolved in glacialacetic acid (36 ml) and 48% HBr (36 ml) and allowed to stir at refluxfor 2 hours. The reaction mixture was poured into an ice water mixturethen basified with 50% NaOH to a pH of 7. The reaction mixture wasfiltered to get a solid which was chromatographed on silica gel, usinghexane: EtOAc (3:2) as eluant, to give the title product (1.6 g) as awhite solid, mp 117-118° C.

Analysis (0.30 H₂ O): Calcd: C 63.87; H 7.04; N 3.55; S 8.12; Found: C63.86; H 7.09; N 3.51; S 8.18; ¹ H NMR (DMSO-d₆), δ: 0.76 (3H, t); 0.81(3H, t); 1.08-2.41 (8H, m); 3.24 (2H, q); 5.83 (1H, d); 6.03 (1H, s);7.31-7.42 (6H, m); 9.60 (3H, bs)

SYNTHETIC EXAMPLE 8 Preparation of(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-ol1,1-dioxide

Chromatography of the reaction from Synthetic Example 7 producedmixtures which were combined and rechromatographed using toluene andtoluene: EtOAc (95:5) as the eluants, to afford the title product (0.29g) as a white solid, mp 155-156° C.

Analysis: Calcd: C 65.48; H 7.24; N 3.47; S 7.95; Found: C 65.58; H7.28; N 3.43; S 8.03; ¹ H NMR (DMSO-d₆), δ: 0.76 (3H, t); 0.81 (3H, t);1.18-2.04 (8H, m); 3.28 (2H,q); 3.82 (3H, s); 5.85 (1H, d); 6.09 (1H,s); 7.31-7.45 (6H, m); 9.43 (1H, s)

SYNTHETIC EXAMPLE 9 Preparation of(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepine-8-ol1,1-dioxide

Chromatography of the reaction mixtures from Synthetic Example 7produced the title compounds of Synthetic examples 7 and 8. One otherproduct was also isolated during the chromatography used in SyntheticExample 8. The title product (0.35 g) was isolated as a white solid, mp165-166° C.

Analysis: Calcd: C 65.48; H 7.24; N 3.47; S 7.95; Found: C 65.32; H7.28; N 3.49; S 8.00; ¹ H NMR (DMSO-d₆), δ: 0.77 (3H, t); 0.81 (3H, t);1.11-2.08 (8H, m); 3.29 (2H, q); 3.44 (3H, s); 5.86 (1H, d); 6.06 (1H,s); 7.32-7.43 (6H, m); 9.73 (1H, s)

SYNTHETIC EXAMPLE 10 Preparation of(+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenl-1,4-benzothiazepine1,1-dioxide

(a) O-(2-benzoyl-5-methoxyphenal)dimethylthiocarbamate Sodium hydride(8.8 g, Aldrich) was added slowly to a solution of2-hydroxy-4-methoxybenzophenone (50.0 g Aldrich) in 300 ml ofdimethylformamide. Hexamethylphosphoramide (43.0 g) was then addeddropwise and stirred at room temperature for 2 hours.Dimethylthiocarbamoyl chloride (37.0 g Aldrich) was added and stirredovernight at 50° C. The reaction mixture was poured into deionized water(300 mL) and extracted with a petroleum ether/chloroform (1:4) mixture.The organic layer was washed with 10% sodium hydroxide, brine andconcentrated to give the title product as a yellow solid (40.0 g). ¹ HNMR was consistent with proposed structure.

(b) S-(2-Benzoyl-5-methoxyphenyl) dimethylthiocarbamate

The product (97.4 g) from step (a) was suspended in tetradecane (500 mL)and heated to an internal temperature of 255° C. for 30 minutes. Aftercooling to room temperature, the reaction mixture was chromatographed onsilica gel using hexane, then hexanes/ethyl acetate (7:3) as eluants toafford the title product (65.0 g) as a tan solid, mp 95-97° C. ¹ H NMRwas consistent with proposed structure.

(c) 2-Mercapto-4-methoxybenzophenone

Potassium hydroxide pellets (20.0 g) were slowly added to a solution ofthe product (28.0 g) from step (b) dissolved in 800 mlmethanol/tetrahydrofuran (1:1). After refluxing for 4 hours, thereaction was cooled to room temperature, methylene chloride was addedand the solution was extracted with 5% hydrochloric acid. The organiclayer was dried and concentrated. Chromatography on silica gel usinghexanes/ethyl acetate (99:1) as the eluant afforded the title product asan orange oil (17.1 g). ¹ H NMR consistent with proposed structure.

(d) Ethyl 2-aminobutyrate hydrochloride

A slurry of 2-aminobutyric acid (100 g Aldrich) in absolute ethanol (300ml) was stirred under nitrogen at 0° C. and thionyl chloride (120.8 g)was added dropwise. The reaction was stirred overnight at 0° C. and thengradually warmed to room temperature. The resulting white slurry washeated under reflux for 3 hours, left to cool for 10 minutes, thenpoured into chilled diethyl ether (600 ml) with hand stirring. Thesuspension was filtered and the solid product dried to give the desiredproduct (150 g) as a white solid. ¹ H NMR consistent with proposedstructure.

(e) Ethyl 2-benzylideneaminobutyrate

A solution of the product from step (d) (149.6 g), magnesium sulphate(74.3 g), and triethylamine (246 ml) in dichloromethane (1500 ml) wasstirred at room temperature under nitrogen and benzaldehyde (94.9 g,Aldrich) was added dropwise. The mixture was stirred at room temperaturefor 3 hours then filtered. The filtrate was concentrated, triturated indiethyl ether, filtered and concentrated to yield the desired product asa yellow oil (174 g). ¹ H NMR consistent with the proposed structure.

(f) (+-)-Ethyl 2-benzylideneamino-2-ethylhexanoate

Sodium hydride (32.5 g, 60% dispersion in oil) and N,N-dimethylformamide(DMF) (700 ml) were stirred under nitrogen at room temperature and asolution of the product from step (e) (178.1 g) in DMF was addeddropwise. After 2 hours stirring at room temperature, a solution ofbutyl iodide (149.5 g) in DMF was added dropwise and the reaction leftstirring for a further 2 hours. The reaction was poured into an ice coldmixture of water (560 ml), diethyl ether (300 ml) and ammonium chloride(120 g). The resulting organic layer was dried over potassium carbonatethen concentrated to give the desired product as a brown oil (220 g).

(g) (+-)-Ethyl 2-amino-2-ethylhexanoate

The product from step (f) (233.0 g), was partitioned between petroleumether and 10% w/w hydrochloric acid (421 ml) and stirred at roomtemperature for 2 hours. The aqueous layer was extracted twice withpetroleum ether and then chilled with ethyl acetate in an ice-salt bath.Sodium hydroxide pellets were added to the mixture until the aqueouslayer was at pH 10. The latter was extracted twice with ethyl acetateand the combined ethyl acetate layers were dried over potassiumcarbonate, then concentrated and vacuum distilled to give the desiredproduct as a colourless oil. ¹ H NMR consistent with the proposedstructure.

(h) (+-)-2-Amino-2-ethylhexan-1-ol

Lithium aluminium hydride (22.2 g) was added to anhydrous diethyl ether(450 ml) under nitrogen. The product from step (g) (129.0 g) was dilutedwith diethyl ether (40 ml) and added dropwise. The reaction was refluxedfor 1 hour then cooled to room temperature. 1M sodium hydroxide (23 ml)was added dropwise followed by deionised water. The resulting suspensionwas filtered and the filtrate concentrated to give the desired productas a colourless oil (87.9 g). ¹ H NMR consistent with the proposedstructure.

(i) (+-)-2-Butyl-2-ethylaziridine

Acetonitrile (150 ml) and the product from step (h) (20.0 g) were mixedunder nitrogen, cooled to 2-3° C. and chlorosulphonic acid (16.0 g,Aldrich) was added dropwise keeping the temperature below 10° C. Thecoolant was removed and the slurry left to stir for 80 minutes at roomtemperature. The reaction was concentrated in vacuo and co-distilledwith water (50 ml). 50% Aqueous sodium hydroxide (55.2 g) and water (50ml) were added and the mixture was distilled at atmospheric pressure.The organic layer was collected from the distillate and dried with solidpotassium hydroxide to give the desired product (12.8 g). ¹ H NMRconsistent with proposed structure.

(j) (+-)-3-Butyl-3-ethyl-8-methoxy-5-phenyl-2,3-dihydrobenzothiazepine

The product (55.2 g) from step (i), in 2,6-lutidine (100 ml), was addedto a solution of the product (118.5 g) from step (c) in 2,6-lutidine(400 ml). The reaction mixture was stirred for 1 hour andp-toluenesulfonic acid (9.0 g) was added and then refluxed with a DeanStark trap for 17 hours. The reaction mixture was concentrated in vacuoand the residue was partitioned between 5% NaHCO₃ and EtOAc. The organiclayer was separated, dried and concentrated to get an oil which waschromatographed on silica gel, using hexane: EtOAc (85:15) as theeluant, to afford the title product (124.3 g) as an orange oil. ¹ H NMRconsistent with the desired structure.

(k)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine

A 1M solution of diborane (40 ml) in THF was added to a solution of theproduct (12.3 g) from step (j) in THF (150 ml). The reaction mixture wasstirred at room temperature for 17 hours, then 6N HCl (50 ml) was addedand the solution was concentrated in vacuo. The residue was basifiedwith 50% NaOH and extracted with EtOAc. The EtOAc layer was separated,dried and concentrated in vacuo to give an oil which was chromatographedon silica gel, using hexanes then toluene as the eluants to afford thedesired product (4.9 g) as a yellow oil. ¹ H NMR consistent with thedesired structure.

(l)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide

A solution of the product (4.9 g) from step (k) in trifluoroacetic acid(50 ml) was added to 30% H₂ O₂ in trifluoroacetic acid (50 ml). Thereaction mixture was stirred at room temperature for 17 hours, thenpoured into deionized water (200 ml) followed by the addition of NaOHpellets until a pH of 14 was obtained. The reaction mixture was warmed,at 45° C., for 3 hours then extracted with dichloromethane. The organiclayer was separated, dried and concentrated to give an oil which waschromatographed on silica gel, using hexane: EtOAc (9:1) as the eluant,to give the title product as a white solid, mp 123-125° C.

Analysis: Calcd: C 68.18; H 7.54; N 3.61; S 8.27; Found: C 68.19; H7.49; N 3.55; S 8.35; ¹ H NMR (DMSO-d₆), δ: 0.73-0.85 (6H, m, CH₃);1.07-1.47 (4H, m, CH₂); 1.48-2.20 (4H, m, CH₂); 2.48-2.53 (1H, d, NH);3.51 (2H, q, CH₂ SO₂); 3.84 (3H, s, OMe); 5.90 (1H, d, CHPh); 6.50 (1H,d, ArH); 7.09-7.20 (1H, m, ArH); 7.32-7.48 (6H, m, ArH)

SYNTHETIC EXAMPLE 11 Preparation of(+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-ol1,1-dioxide

This compound was prepared following the procedure of Synthetic Example7, using the product (4.8 g) from Synthetic Example 10(1).Chromatography on silica gel, using hexane: EtOAc (4:1) as the eluant,gave the title product (1.8 g) as a white solid, mp 130-132° C.

Analysis:Calcd: C67.53; H 7.28; N 3.75; S 8.58; Found: C 67.26; H 7.21;N 3.76; S 8.65; ¹ H NMR (DMSO-d₆), δ: 0.70-0.86 (6H, m); 0.96-1.23 (4H,m); 1.25-1.49 (1H, m); 1.66-1.75 (1H, m); 1.98-2.07 (1H, m); 2.40 (1H,d); 3.33 (2H, q); 5.82 (1H, d); 6.35 (1H, d); 6.77-6.80 (1H, m);7.24-7.38 (6H, m); 10.0 (1H, s)

SYNTHETIC EXAMPLE 12 Preparation of(+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol1,1-dioxide

The product (1.0 g) from Synthetic Example 11 was dissolved in methylenechloride (100 ml), cooled to 0° C. and m-chloroperbenzoic acid (0.55 g,57-86%, Aldrich) was added. The reaction mixture was stirred at ice bathtemperatures for 5 hours then 5% NaHCO₃ was added to neutralize excessacid. The organic layer was separated, dried and concentrated in vacuo.The resulting residue was chromatographed on silica gel, using hexane:EtOAc as the eluant, to afford the title product (0.68 g) as a paleyellow solid, mp 213-214° C.

Analysis: Calcd: C 64.76; H 6.99; N 3.60; S 8.23; Found: C 64.86; H7.03; N 3.63; S 8.31; ¹ H NMR (DMSO-d₆), δ: 0.77-0.89 (6H, m); 1.09-1.64(6H, m); 1.68-2.03 (2H, m); 3.36 (2H, q); 6.30 (1H, s); 6.44 (1H, d);6.82-6.87 (1H, m); 7.27-7.49 (6H, m); 7.89 (1H, s); 10.0 (1H, s)

SYNTHETIC EXAMPLE 13 Preparation of(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methyl-5-phenyl-1,4-benzothiazepine1,1-dioxide

(a) 3-Methylphenyl benzoate

A solution of benzoyl chloride (32.5 g, Aldrich) in ether (200 ml) wasadded dropwise to a stirred solution of m-cresol (25.0 g, Aldrich) andtriethylamine (27.2 g, Aldrich) in ether (500 ml). The reaction mixturewas stirred at room temperature for 1 hour then filtered. The etherealfiltrate was washed with saturated NaHCO₃ and water then dried over Na₂SO₄. The ether layer was separated, dried and concentrated in vacuo togive the desired product (104.0 g) as a white solid, mp 45-47C. ¹ H NMRconsistent with the desired structure.

(b) 2-Hydroxy-4-methylbenzophenone

The product (48 g) from step (a) was melted (at 70° C.) and aluminumchloride (30.2 g) was added in portions. The reaction mixture was heatedto 200° C. for 5 minutes, then cooled to room temperature. The resultingsolid was ground to a powder and slowly added to a mixture of conc. HCl(800 ml) and ice. This mixture was extracted with ether and the etherwas washed with water. The ether layer was separated, dried andconcentrated. The resulting residue was chromatographed on silica gel,using toluene as the eluant, to afford the title product (39 g) as ayellow oil. ¹ H NMR consistent with the desired structure.

(c)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methyl-5-phenyl-1,4-benzothiazepine1,1-dioxide

The product from step (b) was converted to the title product followingthe procedures used in steps (a) to (l) of Synthetic Example 10. Thetitle product was isolated as a white solid, mp 121-122° C.

Analysis: C 71.12; H 7.87; N 3.77; S 8.63; Found: C 71.23; H 7.94; N3.67; S 8.74; ¹ H NMR (DMSO-d₆); δ: 0.77-0.82 (6H, m); 1.16-2.07 (8H,m); 2.36 (3H, s); 3.37 (2H, q); 5.92 (1H, d); 6.47 (1H, d); 7.27-7.39(6H, m); 7.79 (1H, s)

SYNTHETIC EXAMPLE 14 Preparation of(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-carbaldehyde1,1-dioxide

(a)(+-)-7-Bromo-3-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,4-benzothiazepine

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone(16.9 g) was added directly toa benzene solution(300 ml) of the product(as the racemate)(30.2 g) fromSynthetic Example 5 (g). The reaction mixture was stirred at reflux for3 hours, cooled to room temperature. 1N NaOH(200 ml) was added, stirredfor 30 minutes; then the organic layer was separated, washed with brineand 1N NaOH. The benzene layer was separated, dried and concentrated toget an oil which was solubilized in hexane, filtered and concentrated toget the title product (25.8 g) as a red oil. ¹ H NMR consistent with thedesired structure.

(b)(+-)-3-Butyl-7-carbaldehyde-3-ethyl-2,3-dihdro-8-methoxy-5-phenyl-1,4-benzothiazepine

A solution of 1.6M n-butyl lithium (49.0 ml) was to an ice-cooledsolution of the product(25.8 g) from step (a) in hexane (500 ml). Thereaction mixture was stirred for 25 minutes and 4-formylmorpholine(9.0g). The ice bath was removed and the reaction was stirred at roomtemperature for 21/2 hours. The reaction was quenched with a saturatedsolution (250 ml) of NH₄ Cl and stirred for 60 minutes. The organiclayer was separated, dried and concentrated to get 26.9 g of a red oil.Chromatography on silica gel, using hexane:EtOAc(85:15) as eluantafforded the title product (13.9 g) as an orange oil. ¹ H NMR consistentwith the desired structure.

(c)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-metho-5-phenyl-1,4-benzothiazepine-7-carbaldehyde

Ethylene glycol(9.3 g) and pyridinium p-toluenesulfonate(1.3 g) wereadded to a benzene solution (250 ml) of the product(19.0 g) from step(b) and this mixture was refluxed in a Dean Stark trap for 17 hours. Thereaction mixture was cooled to room temperature and treated with aqueousNaHCO₃ (150 ml) for 15 minutes. The organic layer was separated, driedand concentrated to get a thick yellow-orange oil(19.7 g). ¹ H nmr wasconsistent for the dioxolane derivative. This oil was then treated withB₂ H₆, following the procedure cited in Synthetic Example 1 (n), to givethe title product(3.5 g) as an orange oil. ¹ H NMR consistent with thedesired structure.

(d)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-carbaldehyde1,1-dioxide

The product(3.5 g) from step (c) was dissolved in t-butanol/THF (1:4, 60ml) and N-methylmorpholine N-oxide(3.4 g) was added, followed by 2.5 wt.% of OsO₄ in 2-methyl-2-propanol (5.0 ml). The reaction mixture wasstirred at room temperature ofr 17 hours then diluted with EtOAc (250ml). The organic layer was separated, washed with 1N NaOH (2×50 ml) andbrine. The organic layer was separated, dried and concentrated to givean oil which upon trituration in diethyl ether afforded the titleproduct (3.10 g) as a white solid, mp 127-128° C.

Analysis: Calcd: C 66.48; H 7.03; N 3.37; S 7.72; Found: C 66.26; H7.04; N 3.30; S 7.82; ¹ H NMR(DMSO-d₆), δ: 0.73-0.86(6H, m);1.07-2.05(8H, m); 2.65(1H, d); 3.50(2H, q); 4.03(3H, s); 5.91(1H, s);6.92(1H, s); 7.33-7.48(5H, m); 7.74(1H, s); 10.28(1H, s)

SYNTHETIC EXAMPLE 15 Preparation of(+-)-Trans-2-((3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-7-yl)methoxy)ethanol S,S-dioxide

Chromatography of the reaction from Synthetic Example 14 (c) affordedthe corresponding sulfide compound(2.3 g) of the title product as anoil. ¹ H NMR was consistent for the desired structure. This oil was thentreated, according to the procedure shown in Synthetic Example 1 (o), toyield the title product (0.65 g) as a white solid, mp 83-850° C.

Analysis: Calcd: C 65.05; H 7.64; N 3.03; S 6.95; Found: C 64.82; H7.72; N 2.99; S 6.91; ¹ H NMR(DMSO-d6), δ: 0.74-0.86(6H, m);1.07-2.14(8H, m); 2.52(1H, d); 3.35(4H, m); 3.41(2H, q); 3.87(3H, s);4.39(2H, s); 4.54(1H, t); 5.91(1H, d,); 6.64(1H, s); 7.29-7.45(5H, m);7.51(1H, s)

SYNTHETIC EXAMPLE 16 Preparation of(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,4-benzothiazepine-7-carbaldehyde1,1-dioxide

The product (2.0 g) from Synthetic Example 14 (d) was added to glacialacetic acid (20 ml) and 48% HBr (20 ml)) and heated to 150° C. for 24hours. The reaction mixture was concentrated in vacuo, partitionedbetween diethyl ether and 5% NaHCO₃. The organic layer was separated,dried and concentrated to give the title product (0.85 g) as a tansolid, mp 158-159° C.

Analysis: Calcd: C 65.81; H 6.78; N 3.49, S 7.99; Found: C 65.63; H7.04; N 3.32; S 7.74; ¹ H NMR(DMSO-d₆), δ: 0.72-0.85(6H, m);1.07-2.05(8H, m); 2.58(1H, d); 3.46(2H, q); 5.85(1H, d); 6.83(1H, s);7.34-7.47(5H, m); 7.70(1H, s); 10.25(1H, s); 11.33(1H, broad s)

SYNTHETIC EXAMPLE 17 Preparation of(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-thiol1,1-dioxide

The product from Synthetic Example 11 was treated according to theprocedures shown in Synthetic Example 1 (i)-(k) to give the titleproduct as a white solid, mp 108-110° C.

Analysis: Calcd: C 64.75; H 6.99; N 3.60; S 16.46; Found: C 64.83; H7.03; N 3.56; S 16.54; ¹ H NMR(DMSO-d₆), δ: 0.70-0.81(6H, m);1.05-2.06(8H, m); 2.54(1H, d); 3.37(2H, q); 5.85(1H, d); 6.06(1H, broads); 6.40(1H, d); 7.26-7.40(6H, m); 7.90(1H, s)

SYNTHETIC EXAMPLE 18 Preparation of(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-8-sulfonicacid 1,1-dioxide

The product(5.3 g) from Synthetic Example 17 was dissolved in DMSO (13ml). Water (0.3 ml)and 48% HBr (0.2 ml) were then added. The reactionmixture was heated to 120° C., allowing for distillate to be removed,for a period of 4 hours. The reaction mixture was cooled to roomtemperature, diluted with 1N NaOH, and filtered through a sintered glassfunnel. The filtrate was acidified with 1N HCl, the resulting solidswere filtered and dried to get the title product(1.6 g) as a beigesolid, mp>295° C.

Analysis: Calcd. C 57.64; H 6.22; N 3.20; S 14.65; Found: C 57.48; H6.19; N 3.25; S 14.73; ¹ H NMR (DMSO-d₆), S: 0.82-0.95(6H, m);1.32-2.06(8H, m); 2.54(1H, d); 3.93(2H, q); 4.70(1H, broad s); 6.23(1H,s); 6.93(1H, d); 7.60(6H, broad s); 7.84(1H, d); 8.30(1H, s)

SYNTHETIC EXAMPLE 19 Preparation of(7R,9R)-7-Butyl-7-ethyl-6,7,8,9-tetrahydro-9-phenyl-1,3-dioxolo(4,5-H)(1,4)-benzothiazepine5,5-dioxide

The product(0.74 g) from Synthetic Example 7 was dissolved in DMF (5ml). Potassium carbonate(0.50 g) and bromochloroethane(0.47 g) wereadded to the reaction mixture and stirred at 110° C. for 2 hours. Themixture was filtered through Celite, washed with EtOAc, and the filtratewas dried and concentrated to get an oil. Chromatography on silica gel,using hexane:EtOAc(1:1) as eluant, afforded the title product(0.68 g) asa white solid, mp 71-73° C.

Analysis: Calcd. C 65.81; H 6.78; N 3.49; S 7.99; Found: C 65.89; H6.80; N 3.50; S 8.08; ¹ H NMR(DMSO-d₆), δ: 0.71-0.85(6H, m);1.05-2.12(8H, m); 2.49(1H, d); 3.25(2H, q); 3.42(2H, s); 5.91(1H, d);6.06(1H, s);7.27-7.41(6H, m)

SYNTHETIC EXAMPLE 20 Preparation of(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8.9-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide

(a) 2-Hydroxy-3,4-methoxybenzaldehyde

Aluminum chloride(21.8 g) was added, spatula-wise, to an ice-chilledsolution of benzoyl chloride(22.1 g) and 1,2,3-trimethoxybenzene(25.0 g)in 1,2-dichloroethane (250 ml). The reaction mixture was stirred at 0-5°C. for 3 hours, then heated to reflux for 2 hours. The reaction mixturewas then poured onto ice/concentrated HCl (100 ml) and stirred for 30minutes, then extracted with diethyl ether. The organic layer wasseparated, dried and concentrated to get a solid(23.0 g). Chromatographyon silica gel , using toluene:EtOAc(9:1) as eluant, afforded the titleproduct(18.0 g) as a white solid, mp 127-128°C. 1H NMR consistent withthe desired structure.

(b)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide

The product from step (a) was converted to the title product followingthe procedures used in steps (a) to (l) of Synthetic Example 10. Thetitle product was isolated as a white solid, mp 142-144° C.

Analysis: C 66.16; H 7.48; N 3.35; S 7.68; Found: C 66.03; H 7.53; N3.28; S 7.77; ¹ H NMR(DMSO-d₆), δ: 0.64(3H, t); 0.81(3H, t);0.87-2.08(8H, m); 2.42(1H, d); 3.73(2H, q); 3.75(3H, s); 3.79(3H, s);5.50(1H, d); 6.05(1H, d); 6.97(1H, d); 7.27-7.41(5H, m)

SYNTHETIC EXAMPLE 21 Preparation of(3R,5R)-3-butyl-3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-7,8-dimethoxy-1,4-benzothiazpin-4-ol1,1-dioxide

(a) 2-Hydroxy-4,5-Dimethoxy-4'-fluorobenzophenone

A 1.0M solution of boron trichloride(142 ml) in dichioromethane wasadded to 4-fluorobenzoyl chloride(16.8 ml) in benzene (200 ml). Next,3,4-dimethoxyphenol(20.0 g) in benzene (100 ml) was added and thereaction mixture was stirred at room temperature for 2 hours. Themixture was then poured onto ice water and allowed to stir for 15minutes, then 1N HCl (500 ml) was added and stirred at room temperaturefor 17 hours. The reaction mixture was extracted with EtOAc, the EtOAcwas separated, concentrated and dried to give the title product(41.7 g)as an orange solid. ¹ H NMR consistent with desired structures.

(b)(3R,5R)-3-buty-3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-7,8-dimethoxy-1,4-benzothiazpin-4-ol1,1-dioxide

The product from step (a) was converted to the title product followingthe procedures used in steps (a) to (o) of Synthetic Example 1 and theprocedure used in Synthetic Example 2. The title product was isolated aswhite solid, mp 170-171° C.

Analysis: C 61.18; H 6.70; N 3.10; S 7.10; Found: C 61.28; H 6.78; N2.99; S 7.27; ¹ H NMR(DMSO-d₆), δ: 0.75-0.85(6H, m); 1.07-2.04(8H, m);3.35(2H, q); 3.42(3H, s); 3.81(3H, s); 6.07(1H, s); 6.33(1H, s);7.22(2H, t); 7.39(1H, s); 7.40-7.50(2H, m); 7.96(1H, s)

SYNTHETIC EXAMPLES 22-54

Each of the following examples was prepared by a method analagous tothat of Synthetic Example 1, by one of the other exemplified routes orby chemical methods known to those in the art. In all cases, ¹ H NMR andelemental analysis were consistent with the proposed structure.

(22) (+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl1,4-benzothiazepine-7-methanol S,S-dioxide, mp 122-123° C.

(23)(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-nitro-5-phenyl-1,4-benzothiazepine1,1-dioxide 0.40 hydrate, mp 122-123° C.

(24)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-(methoxymethyl)-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 118-119° C.

(25)(+-)-Trans-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide 0.40 hydrate, mp 137-138° C.

(26)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 169-170° C.

(27)(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-7,8-diyldiacetate 1,1-dioxide, mp 79-81° C.

(28)(8R,10R)-8-Butyl-8-ethyl-2,3,7,8,9,10-hexahydro-10-1,4-dioxono(2,3-H)(1,4)-benzothiazepine6,6-dioxide, mp 82° C.

(29)(3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1 dioxide 0.20 hydrate, mp 110-111° C.

(30)(+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 45-54° C.

(31)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-(methylthio)-5-phenyl-1,4-benzothiazepine1,1-dioxidehydrochloride, mp 194-197° C.

(32)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide hydrochloride, mp 178-181° C.

(33)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-carbaldehyde1,1-dioxide, mp 165-170° C.

(34)3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-ylaspartate

(35)3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide,mp 163-164° C.

(36)3,3-Diethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-8-methoxy-1,4-benzothiazepine-1,1-dioxidemp 101-103° C.

(37)3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide,mp 132-133° C.

(38)3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4,8-diol-1,1-dioxide,mp 225-227° C.

(39)(RS)-3,3-Diethyl-2,3,4,5-tetrahydro4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 205-206° C.

(40)(+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin4ol1,1-dioxide, mp 149-150° C.

(41)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothazepin-4-ol1,1-dioxide, mp 109-115° C.

(42)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide, mp 84-96° C.

(43)(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4,7,8-triol-1,1-dioxide,mp 215-220° C.

(44)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5phenyl-1,4-benzothiazepine1,1-dioxide, mp 169-87° C.

(45)(+-)-Trans-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-7,8-dimethoxy-1,4-benzothiazepin-4-ylacetate S,S-dioxide, mp 154-156° C.

(46)3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide,mp 177-178° C.

(47)3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide

(48)3,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide

(49)(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-ylhydrogen sulfate, mp 196.5-200° C.

(50)(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yldihydrogen phosphate

(51)3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-ylhydrogensulfate

(52)3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yldihydrogenphosphate

(53)(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-ylaspartate

Biological Assay

In vivo inhibition of bile acid uptake

Inhibiting intestinal bile acid absorption with bile acid sequestrantsor surgically with partial ileal bypass surgery is an effective way todecrease plasma LDL cholesterol concentration. Another approach todecreasing bile acid absorption is inhibiting the ileal bile acid activeuptake transport system. It has been shown that this inhibition, asmeasured by the fecal excretion of bile acids results inhypocholesterolemic activity. (1) Lewis, M. C.; Brieaddy, L. E.; andRoot, C. Effects of 2164U90 on Ileal Bile Acid Absorption and SerumCholesterol in Rats and Mice. J. Lipid. Research., 1995, 36, 1098-1105.

Fecal Excretion of Bile Acids

Male Spraque-Dawley rats weighing 220-260 g were housed in individualcages and fed normal chow. The rats were divided into 6 treatment groupsof 10 to 12 rats per group. The rats were dosed by oral gavage(1 mL/100g body weight) with test compounds as a suspension in 0.5%methylcellulose at 9:00 am and 3:30 pm for two days. The control groupreceived 0.5% methylcellulose. Two hours after the morning dose on daytwo, the rats were given a trace amount(1.3 nmoles) of 23, 25-⁷⁵Se-homocholic acid taurine(⁷⁵ SeHCAT) in 1.0 mL saline orally. ⁷⁵SeHCAT, a synthetic gamma emitting bile acid analog which is absorbed bythe ileal bile acid uptake system similar to taurocholic acid, has beenused clinically as a measure of ileal bile acid absorptionl,¹,2. Feceswere collected over the 24 hr following ⁷⁵ SeHCAT administration. Fecalcontent of ⁷⁵ SeHCAT was determined using a Packard Auto-Gamma 5000Series gamma-counter. Representative data are tabulated in Table 1 asthe % inhibition of ⁷⁵ SeHCAT.

(1) Galatola, G.; Jazrawi, R. P.; Bridges, C.; Joseph, A. E. A. andNorthfield, T. C. Direct Measurement of First-Pass Ileal Clearance of aBile Acid in Humans. Gastroenterology. 1991, 100, 1100-1105.

(2) Ferraris, R.; Galatoa, G.; Barlotta, A; Pellerito, R.; Fracchia, M.;Cottino, F. and De La Pierre, M. Measurement of Bile Acid Half-LifeUsing ⁷⁵ Se!HCAT in Health and Intestinal Diseases. Dig. Dis. Sci. 1992,37, 225-232.

                  TABLE 1    ______________________________________    (% Inhibition of .sup.75 SeHCAT)    Compound of  Dose (mg/kg)    Example      1.0          0.3   0.1    ______________________________________     1                        51    54     7                        65    72     9                        80    70    10                        53    33    11                        72    71    14           56           41    16           44           34    18           39           12    24           49           24    45           26            6    ______________________________________

In comparison, the most active compound specifically disclosed inInternational Patent Application No. WO 93/16055 produced a 9%inhibition of ⁷⁵ SeHCAT at 1.0 mg/kg in this assay.

Pharmaceutical Composition Examples

In the following Examples, the active compound can be any compound offormula (I) and/or a pharmaceutically acceptable salt, solvate, orphysiologically finctional derivative thereof. The active compound ispreferably(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1-4-benzothiazepine1,1-dioxide or one of the compounds of Synthetic Examples 2 to 53.

(i) Tablet compositions

The following compositions A and B can be prepared by wet granulation ofingredients (a) to (c) and (a) to (d) with a solution of povidone,followed by addition of the magnesium stearate and compression.

Composition A

    ______________________________________                      mg/tablet                             mg/tablet    ______________________________________    (a)    Active ingredient                            250      250    (b)    Lactose B.P.     210      26    (c)    Sodium Starch Glycollate                             20      12    (d)    Povidone B.P.     15       9    (e)    Magnesium Stearate                             5        3                            500      300    ______________________________________

Composition B

    ______________________________________                      mg/tablet                             mg/tablet    ______________________________________    (a)    Active ingredient                            250      250    (b)    Lactose 150      150      --    (c)    Avicel PH 101     60      26    (d)    Sodium Starch Glycollate                             20      12    (e)    Povidone B.P.     15       9    (f)    Magnesium Stearate                             5        3                            500      300    ______________________________________

Composition C

    ______________________________________                   mg/tablet    ______________________________________    Active ingredient                     100    Lactose          200    Starch            50    Povidone          5    Magnesium Stearate                      4                     359    ______________________________________

The following compositions D and E can be prepared by direct compressionof the admixed ingredients. The lactose used in composition E is of thedirect compression type.

Composition D

    ______________________________________                     mg/tablet    ______________________________________    Active ingredient  250    Magnesium Stearate  4    Pregelatinised Starch NF15                       146                       400    ______________________________________

Composition E

    ______________________________________                   mg/tablet    ______________________________________    Active ingredient                     250    Magnesium Stearate                      5    Lactose          145    Avicel           100                     500    ______________________________________

Composition F (Controlled release composition)

    ______________________________________                         mg/tablet    ______________________________________    (a)      Active ingredient 500    (b)      Hydroxypropylmethylcellulose                               112             (Methocel K4M Premium)    (c)      Lactose B.P.       53    (d)      Povidone B.P.C.    28    (e)      Magnesium Stearate                                7                               700    ______________________________________

The composition can be prepared by wet granulation of ingredients (a) to(c) with a solution of povidone, followed by addition of the magnesiumstearate and compression.

Composition G (Enteric-coated tablet)

Enteric-coated tablets of Composition C can be prepared by coating thetablets with 25 mg/tablet of an enteric polymer such as celluloseacetate phthalate, polyvinylacetate phthalate,hydroxypropylmethyl-cellulose phthalate, or anionic polymers ofmethacrylic acid and methacrylic acid methyl ester (Eudragit L). Exceptfor Eudragit L, these polymers should also include 10% (by weight of thequantity of polymer used) of a plasticizer to prevent membrane crackingduring application or on storage. Suitable plasticizers include diethylphthalate, tributyl citrate and triacetin.

Composition H (Enteric-coated controlled release tablet)

Enteric-coated tablets of Composition F can be prepared by coating thetablets with 50 mg/tablet of an enteric polymer such as celluloseacetate phthalate, polyvinylacetate phthalate,hydroxypropylmethyl-cellulose phthalate, or anionic polymers ofmethacrylic acid and methacrylic acid methyl ester (Eudragit L). Exceptfor Eudragit L, these polymers should also include 10% (by weight of thequantity of polymer used) of a plasticizer to prevent membrane crackingduring application or on storage. Suitable plasticizers include diethylphthalate, tributyl citrate and triacetin.

(ii) Capsule compositions

Composition A

Capsules can be prepared by admixing the ingredients of Composition Dabove and filling two-part hard gelatin capsules with the resultingmixture. Composition B (jnfa) may be prepared in a similar manner.

Composition B

    ______________________________________                        mg/capsule    ______________________________________    (a)        Active ingredient                              250    (b)        Lactose B.P.   143    (c)        Sodium Starch Glycollate                               25    (d)        Magnesium Stearate                               2                              420    ______________________________________

Composition C

    ______________________________________                       mg/capsule    ______________________________________    (a)        Active ingredient                              250    (b)        Macrogol 4000 BP                              350                              600    ______________________________________

Capsules can be prepared by melting the Macrogol 4000 BP, dispersing theactive ingredient in the melt and filling two-part hard gelatin capsulestherewith.

Composition D

    ______________________________________                   mg/capsule    ______________________________________    Active ingredient                     250    Lecithin         100    Arachis Oil      100                     450    ______________________________________

Capsules can be prepared by dispersing the active ingredient in thelecithin and arachis oil and filling soft, elastic gelatin capsules withthe dispersion.

Composition E (Controlled release capsule)

    ______________________________________                        mg/capsule    ______________________________________    (a)       Active ingredient                              250    (b)       Microcrystalline Cellulose                              125    (c)       Lactose BP      125    (d)       Ethyl Cellulose  13                              513    ______________________________________

The controlled release capsule composition can be prepared by extrudingmixed ingredients (a) to (c) using an extruder, then spheronising anddrying the extrudate. The dried pellets are coated with a releasecontrolling membrane (d) and filled into two-part, hard gelatincapsules.

Composition F (Enteric capsule)

    ______________________________________                        mg/capsule    ______________________________________    (a)       Active ingredient                              250    (b)       Microcrystalline Cellulose                              125    (c)       Lactose BP      125    (d)       Cellulose Acetate Phthalate                               50    (e)       Diethyl Phthalate                               5                              555    ______________________________________

The enteric capsule composition can be prepared by extruding mixedingredients (a) to (c) using an extruder, then spheronising and dryingthe extrudate. The dried pellets are coated with an enteric membrane (d)containing a plasticizer (e) and filled into two-part, hard gelatincapsules.

Composition G (Enteric-coated controlled release capsule)

Enteric capsules of Composition E can be prepared by coating thecontrolled-release pellets with 50 mg/capsule of an enteric polymer suchas cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropylmethylcellulose phthalate, or anionic polymers ofmethacrylic acid and methacrylic acid methyl ester (Eudragit L). Exceptfor Eudragit L, these polymers should also include 10% (by weight of thequantity of polymer used) of a plasticizer to prevent membrane crackingduring application or on storage. Suitable plasticizers include diethylphthalate, tributyl citrate and triacetin.

(iii) Intravenous injection composition

    ______________________________________    Active ingredient         0.200 g    Sterile, pyrogen-free phosphate buffer (pH 9.0) to                                10 ml    ______________________________________

The active ingredient is dissolved in most of the phosphate buffer at35-40° C., then made up to volume and filtered through a sterilemicropore filter into sterile 10 ml ylass vials (Type 1) which aresealed with sterile closures and overseals.

(iv) Intramuscular injection composition

    ______________________________________    Active ingredient       0.20 g    Benzyl Alcohol          0.10 g    Glycofurol 75           1.45 g    Water for Injection q.s. to                            3.00 ml    ______________________________________

The active ingredient is dissolved in the glycofurol. The benzyl alcoholis then added and dissolved, and water added to 3 ml. The mixture isthen filtered through a sterile micropore filter and sealed in sterile 3ml ylass vials (Type 1).

(v) Syrup composition

    ______________________________________    Active ingredient    0.25         g    Sorbitol Solution    1.50         g    Glycerol             1.00         g    Sodium Benzoate      0.005         g    Flavour              0.0125       ml    Purified Water q.s. to                         5.0          ml    ______________________________________

The sodium benzoate is dissolved in a portion of the purified water andthe sorbitol solution added. The active ingredient is added anddissolved. The resulting solution is mixed with the glycerol and thenmade up to the required volume with the purified water.

(vi) Suppository composition

    ______________________________________                          mg/suppository    ______________________________________    Active ingredient        250    Hard Fat, BP (Witepsol H15-Dynamit NoBel)                            1770                            2020    ______________________________________

One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at 45°C. maximum. The active ingredient is sifted through a 200 lm sieve andadded to the molten base with mixing, using a Silverson fitted with acutting head, until a smooth dispersion is achieved. Maintaining themixture at 45° C., the remaining Witepsol H15 is added to the suspensionwhich is stirred to ensure a homogenous mix. The entire suspension isthen passed through a 250 lm stainless steel screen and, with continuousstirring, allowed to cool to 40° C. At a temperature of 38-40° C., 2.02g aliquots of the mixture are filled into suitable plastic moulds andthe suppositories allowed to cool to room temperature.

(vii) Pessarv composition

    ______________________________________                    mg/pessary    ______________________________________    Active ingredient (63 lm)                      250    Anhydrous Dextrose                      380    Potato Starch     363    Magnesium Stearate                       7                      1000    ______________________________________

The above ingredients are mixed directly and pessaries prepared bycompression of the resulting mixure.

(viii) Transdermal composition

    ______________________________________    Active ingredient 200 mg    Alcohol USP        0.1 ml    Hydroxyethyl cellulose    ______________________________________

The active ingredient and alcohol USP are gelled with hydroxyethylcellulose and packed in a transdermal device with a surface area of 10cm².

I claim:
 1. The compounds of the formula (IVa) ##STR12## wherein R¹ is astraight chained C₁₋₆ alkyl group;R² is a straight chained C₁₋₆ alkylgroup; R³ is hydrogen or a group OR¹¹ in which R¹¹ is hydrogen,optionally substituted C₁₋₆ alkyl or a C₁₋₆ alkylcarbonyl group; R⁴ isun-substituted phenyl; R⁵ is hydrogen; R⁶ and R⁸ are independentlyselected from hydrogen, C₁₋₄ alkyl optionally substituted by fluorine,C₁₋₄ alkoxy, halogen, or hydroxy; R⁷ is selected from OR¹⁵, S(O)_(n)R¹⁵, OCOR¹⁵, OCF₃, OCN, SCN, CHO, OCH₂ OR¹⁵, OCH═CHR¹⁵, O(CH₂ CH₂O)nR¹⁵, O(CH₂)_(p) SO₃ R¹⁵, O(CH₂)_(p) NR¹² R¹³ and O(CH₂)_(p) N⁺ R¹²R¹³ R¹⁴ wherein p is an integer from 1-4, n is an integer from 0-3, andR¹², R¹³, R¹⁴, and R¹⁵ are independently selected from hydrogen andoptionally substituted C₁₋₆ alkyl; R⁹ and R¹⁰ are the same or differentand each is selected from hydrogen or C₁₋₆ alkyl; andsalts, solvates andphysiologically functional derivatives thereof.
 2. A compound selectedfrom the group consistingof:(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4,-benzothiazepin-4-ol1,1-dioxide;(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7,8-diol1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-7-ol1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-thiol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-sulfonicacid 1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;(3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide;(+-)-Trans-3-buty-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide hydrochloride;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-carbaldehyde-1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4,8-diol1,1-dioxide;(RS)-3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4-ol-1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1.4-benzothiazepin-4-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4,7,8-triol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;3,3Dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-ylhydrogen sulfate; and3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-ylhydrogen sulfate. 3.(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide, or a salt, solvate, or physiologically functionalderivative thereof.
 4. The compounds of claim 1 wherein R⁵ and R⁸ areboth hydrogen; R⁶ is C₁₋₄ alkyl optionally substituted by fluorine, C₁₋₄alkoxy, halogen or hydroxy; and R⁷ is C₁₋₄ alkoxy, halogen, hydroxy, or--S(O)_(n) R¹⁵.
 5. The compounds of claim 1 wherein R⁵ and R⁸ are bothhydrogen; R⁶ is methyl, methoxy, hydroxy, trifluoromethyl or chloro; andR⁷ is methoxy, hydroxy, or --S(O)_(n) R¹⁵.
 6. The compounds of claim 1wherein R⁵ and R⁸ are both hydrogen; R⁶ is methoxy, hydroxy, or chloro;and R⁷ is methoxy, hydroxy, or --S(O)_(n) R¹⁵.
 7. The compounds of claim1 wherein R¹ is n-butyl; R² is ethyl; R³, R⁵, R⁸, R⁹, and R¹⁰ arehydrogen; R⁶ is methoxy, or hydroxy; and R⁷ is methoxy, hydroxy, or--S(O)_(n) R¹⁵. 8.(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide, or a salt, solvate, or physiologically functionalderivative thereof. 9.(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-sulfonicacid 1,1-dioxide, or a salt, solvate, or physiologically functionalderivative thereof.
 10. A method of inhibiting the absorption of bileacids from the intestine of a mammal which comprises administering aneffective bile acid absorption inhibiting amount of a compound of claim1 to the mammal.
 11. A method of reducing the blood plasma or serumconcentrations of LDL and VLDL cholesterol in a mammal which comprisesadministering an effective cholesterol reducing amount of a compound ofclaim 5 to the mammal.
 12. A method of reducing the concentrations ofcholesterol and cholesterol ester in the blood plasma or serum of amammal which comprises administering an effective cholesterol andcholesterol ester reducing amount of a compound of claim 1 to themammal.
 13. A method of increasing the fecal excretion of bile acids ina mammal which comprises administering an effective bile acid fecalexcretion increasing amount of a compound of claim 1 to the mammal. 14.A method of reducing the incidence of coronary heart disease-relatedevents in a mammal which comprises administering an effective coronaryheart disease-related events reducing amount of a compound of claim 1 tothe mammal.
 15. A method of reducing the concentration of cholesterol inthe blood plasma or serum of a mammal which comprises administering aneffective cholesterol reducing amount of a compound of claim 1 to themammal.
 16. A method of treating a clinical condition in a mammal forwhich a bile acid uptake inhibitor is indicated which comprises,administering to a mammal an effective bile acid uptake inhibitionamount of a compound of formula (IVa): ##STR13## wherein R¹ is astraight chained C₁₋₆ alkyl group;R² is a straight chained C₁₋₆ alkylgroup; R³ is hydrogen or a group OR¹¹ in which R¹¹ is hydrogen,optionally substituted C₁₋₆ alkyl or a C₁₋₆ alkylcarbonyl group; R⁴ isun-substituted phenyl; R⁵ is hydrogen; R⁶ and R⁸ are independentlyselected from hydrogen, C₁₋₄ alkyl optionally substituted by fluorine,C₁₋₄ alkoxy, halogen, or hydroxy; R⁷ is selected from OR¹⁵, S(O)_(n)R¹⁵, OCOR¹⁵, OCF₃, OCN, SCN, CHO, OCH₂ OR¹⁵, OCH═CHR¹⁵, O(CH₂ CH₂O)nR¹⁵, O(CH₂)_(p) SO₃ R¹⁵, O(CH₂)_(p) NR¹² R¹³ and O(CH₂)_(p) N⁺ R¹²R¹³ R¹⁴ wherein p is an integer from 1-4, n is an integer from 0-3, andR¹², R¹³, R¹⁴, and R¹⁵ are independently selected from hydrogen andoptionally substituted C₁₋₆ alkyl; R⁹ and R¹⁰ are the same or differentand each is selected from hydrogen or C₁₋₆ alkyl; and salts, solvatesand physiologically functional derivatives thereof.
 17. The method ofclaim 16 wherein the compound of formula (IVa) is selectedfrom:(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4,-benzothiazepin-4-ol1,1-dioxide;(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7,8-diol1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-7-ol1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-thiol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-sulfonicacid 1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;(3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide hydrochloride;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-carbaldehyde-1,1-dioxide;3.3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4,8-diol1,1-dioxide;(RS)-3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4,7,8-triol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;3,3Dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-ylhydrogen sulfate; and3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-ylhydrogen sulfate.
 18. The method of claim 17 wherein the compound isselected from:(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetradhydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-sulfonicacid 1,1-dioxide; or a salt, solvate, or physiologically functionalderivative thereof.
 19. A method of treating a hyperlipidemic conditionin a mammal which comprises, administering to the mammal an effectivehyperlipidemic treatment amount of a compound of formula (IVa):##STR14## wherein R¹ is a straight chained C₁₋₆ alkyl group;R² is astraight chained C₁₋₆ alkyl group; R³ is hydrogen or a group OR¹¹ inwhich R¹¹ is hydrogen, optionally substituted C₁₋₆ alkyl or a C₁₋₆alkylcarbonyl group; R⁴ is un-substituted phenyl; R⁵ is hydrogen; R⁶ andR⁸ are independently selected from hydrogen, C₁₋₄ alkyl optionallysubstituted by fluorine, C₁₋₄ alkoxy, halogen, or hydroxy; R⁷ isselected from OR¹⁵, S(O)_(n) R¹⁵, OCOR¹⁵, OCF₃, OCN, SCN, CHO, OCH₂OR¹⁵, OCH═CHR¹⁵, O(CH₂ CH₂ O)_(n) R¹⁵, O(CH₂)_(p) SO₃ R¹⁵, O(CH₂)_(p)NR¹² R¹³ and O(CH₂)_(p) N⁺ R¹² R¹³ R¹⁴ wherein p is an integer from 1-4,n is an integer from 0-3, and R¹², R¹³, R¹⁴, and R¹⁵ are independentselected from hydrogen and optionally substituted C₁₋₆ alkyl; R⁹ and R¹⁰are the same or different and each is selected from hydrogen or C₁₋₆alkyl; and salts, solvates and physiologically functional derivativesthereof.
 20. The method of claim 19 wherein the compound of formula(IVa) is selectedfrom:(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4,-benzothiazepin-4-ol1,1-dioxide;(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7,8-diol1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-7-ol1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-thiol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-sulfonicacid 1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;(3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide hydrochloride;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-carbaldehyde-1,1-dioxide;3.3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4,8-diol1,1-dioxide;(RS)-3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide-;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4,7,8-triol1,1dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;3,3Dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-ylhydrogen sulfate; and3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-ylhydrogen sulfate.
 21. The method of claim 20 wherein the compound isselectedfrom:(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetradhydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-sulfonicacid 1,1-dioxide; or a salt, solvate, or physiologically functionalderivative thereof.
 22. The method of claim 19 wherein thehyperlipidemic condition is atherosclerosis.
 23. A pharmaceuticalcomposition comprising a compound of formula (IVa): ##STR15## wherein R¹is a straight chained C₁₋₆ alkyl group;R² is a straight chained C₁₋₆alkyl group; R³ is hydrogen or a group OR¹¹ in which R¹¹ is hydrogen,optionally substituted C₁₋₆ alkyl or a C₁₋₆ alkylcarbonyl group; R⁴ isun-substituted phenyl; R⁵ is hydrogen; R⁶ and R⁸ are independentlyselected from hydrogen, C₁₋₄ alkyl optionally substituted by fluorine,C₁₋₄ alkoxy, halogen, or hydroxy; R⁷ is selected from OR¹⁵, S(O)_(n)R¹⁵, OCOR¹⁵, OCF₃, OCN, SCN, CHO, OCH₂ OR¹⁵, OCH═CHR¹⁵, O(CH₂ CH₂O)nR¹⁵, O(CH₂)_(p) SO₃ R¹⁵, O(CH₂)_(p) NR¹² R¹³ and O(CH₂)_(p) N⁺ R¹²R¹³ R¹⁴ wherein p is an integer from 1-4, n is an integer from 0-3, andR¹², R¹³, R¹⁴, and R¹⁵ are independently selected from hydrogen andoptionally substituted C₁₋₆ alkyl; R⁹ and R¹⁰ are the same or differentand each is selected from hydrogen or C₁₋₆ alkyl; and salts, solvatesand physiologically functional derivatives thereof, at least onepharmaceutically acceptable carrier, and optionally one or more otherphysiologically active agents.
 24. The pharmaceutical composition ofclaim 23 wherein the compound of formula (lVa) is selectedfrom:(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-berizothiazepine1,1-dioxide;(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7,8-diol1,1 dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-7-ol1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-thiol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-sulfonicacid 1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,4-benzothiazepine-1,1-dioxide;(3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyt-1,4-benzothiazepine1,1-dioxide;(+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide hydrochloride;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-carbaldehyde-1,1-dioxide;3.3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4,8-diol1,1-dioxide; (RS)-3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine 1,1-dioxide;(+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4-ol-1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-1,4-benzothiazepin-4-ol1,1-dioxide;(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4,7,8-triol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-trimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;3,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-ylhydrogen sulfate; and 3.3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-ylhydrogen sulfate.
 25. The pharmaceutical composition of claim 24 whereinthe compound is selectedfrom:(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetradhydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide;(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide;(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-sulfonicacid 1,1-dioxide; or a salt, solvate, or physiologically functionalderivative thereof.
 26. The pharmaceutical composition of claim 23 whichis an enteric coated tablet or capsule.
 27. The pharmaceuticalcomposition of claim 24 which is an enteric coated tablet or capsule.28. The pharmaceutical composition of claim 25 which is an entericcoated tablet or capsule.